Method of treating muscular tension, muscle spasticity and anxiety with 3-aryloxy and 3-arylthioazetidinecarboxamides

ABSTRACT

A method of treating animals to obtain muscle relaxation and/or to relieve anxiety is disclosed utilizing novel and known 3-aryloxy and 3-arylthioazetidinecarboxamides having the formula: ##STR1## wherein Z is oxygen or sulfur; B is oxygen or sulfur; Ar is pyridyl or halo substituted pyridyl, phenyl or substituted phenyl; R 1  and R 2  are hydrogen, loweralkyl, aryl, allyl groups, propargyl, cycloalkyl, loweralkylcycloalkyl, cycloalkylloweralkyl, arylloweralkyl and diloweralkylaminoalkyl, and R 1  and R 2  when taken together with the adjacent nitrogen atom may form a heterocyclic amine radical; R 3  is hydrogen, loweralkyl, aryl or arylloweralkyl, and the geometrical isomers thereof and pharmaceutical salts thereof and hydrates thereof when they are possible.

This is a division of application Ser. No. 06/921,521, filed Oct. 22,1986, now U.S. Pat. No. 5,068,231 and a continuation-in-part applicationof copending U.S. patent application Ser. No. 706,632 filed Feb. 28,1985 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to a method of treating muscle tension, musclespasticity and anxiety in living animals, including humans, with3-aryloxy and 3-arylthioazetidinecarboxamides, certain of which arenovel, and a novel process for preparing3-phenoxy-1-azetidinecarbonylchloride chemical intermediates.

2. Information Disclosure Statement

Certain of the compounds useful in the method of the present inventionare disclosed in U.S. Pat. No. 4,226,861 as having anticonvulsantactivity and use in treating epilepsy having the formula: ##STR2##wherein R is loweralkyl and R¹ is hydrogen, aminocarbonyl ortrifluoromethyl.

Certain other of the compounds useful in the present invention aredisclosed in U.S. Pat. No. 4,571,393, as having anticonvulsant activityand having the formula: ##STR3## wherein R¹ =H, F, loweralkyl,loweralkoxy, trifluoromethyl, acetyl, or aminocarbonyl. A U.S.application from an earlier parent U.S. application Ser. No. 409,476filed Aug. 19, 1982, now abandoned, which application stated that thecompounds of U.S. Pat. No. 4,226,861, mentioned above, have musclerelaxant property and based on another less reliable test stated thatthe compounds in U.S. application Ser. No. 409,476 do not have musclerelaxant activity at an effective anticonvulsant dosage. The subjectmatter of U.S. application Ser. No. 409,476 subsequently was publishedin European patent application 102-194-A on Mar. 7, 1984.

A U.S. application Ser. No. 706,621 filed on Feb. 28, 1985, discloses agroup of novel compounds within the generic formula of the presentinvention and others wherein R¹ and R² encompass aminoloweralkylradicals as having anticonvulsant activity and methods and compositionsfor treating epilepsy.

One novel aspect of the present invention is a process for preparing1-chlorocarbonyl-3-aryloxyazetidine intermediates from phosgene and1-diphenylmethyl or 1-(1-phenylethyl)-3-aryloxyazetidines. U.S. Pat. No.4,547,514 discloses preparation of1-chlorocarbonyl-3-aryloxypyrrolidines by reaction of1-benzyl-3-aryloxypyrrolidines and phosgene. However, analogousapplication of the use of the 1-benzyl group in correspondingpreparation of 1-chlorocarbonyl azetidine compounds there are two majorconsiderations: 1) synthesis of 1-benzyl-3-phenoxyazetidines is highlyimpractical, and 2) by-product benzyl chloride is extremely difficult toseparate and any residual benzyl chloride reacts with amidating agents.Prior to the present invention, displacement of 1-diphenylmethyl or1-(1-phenylethyl) groups of azetidine compounds was unknown and thesegroups were thought to be too bulky for displacement by phosgene.

U.S. Pat. No. 4,031,221 discloses reaction of 1-benzyl and1-diphenylmethyl-3-phenoxy heterocyclic amines with alkyl orphenylchloroformate to prepare 1-alkylcarbonyl or 1-phenylcarbonylderivatives, in particular,1-diphenylmethyl-3-(4-trifluorophenoxy)azetidine withphenylchloroformate to give 1-phenoxycarbonyl-3-(p-fluorophenoxy)azetidine. Such phenoxycarbonyl compounds do not, of course, reactdirectly with amines as do the chlorocarbonyl intermediates prepared bythe novel process of this invention. Furthermore, the foregoing reactionwith the chloroformates leads to substantial azetidine ring opening notseen in the phosgene reaction and the phosgene reaction occurs at alower temperature in a short time.

SUMMARY OF THE INVENTION

The 3-aryloxy and 3-arylthioazetidinecarboxamides useful in the methodof treating muscle tension, muscle spasticity and/or anxiety in animalsof this invention have the formula: ##STR4## wherein Ar is selected frompyridyl in any of its positions, including pyridyl substituted by halo,from phenyl or phenyl substituted by 1 or 2 radicals selected fromchloro, bromo, iodo, fluoro, loweralkyl, loweralkoxy, nitro,aminocarbonyl, or trifluoromethyl;

B is oxygen or sulfur;

Z is oxygen or sulfur;

R¹ and R² may be the same or different and are selected from hydrogen,loweralkyl, aryl, allyl, substituted allyl, propargyl, cycloalkyl,loweralkylcycloalkyl, cycloalkylloweralkyl, arylloweralkyl anddiloweralkylaminoloweralkyl, and R¹ and R² when taken together with theadjacent nitrogen atom may form a heterocyclic amine radical, includingazetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolyl,piperazinyl, (halophenyl)piperidin-1-yl,phenyl-1,2,3,6-tetrahydropyridin-1-yl, phenylpiperidin-1-yl,hydroxypiperidin-1-yl, 4-morpholino, 4-(3,5-diloweralkyl) morpholino,4-(2,6-diloweralkyl)morpholino, 1,2,3,6-tetrahydropyridin-1-yl,(halophenyl) (hydroxy)piperidin-1-yl, pyrrolo[1,2-a]pyrazin-2-yl,homopiperazinyl, 4-substituted piperazinyl, and 4-substitutedhomopiperazinyl.

R³ is selected from hydrogen, loweralkyl, aryl or arylloweralkyl; thegeometrical isomers, including cis, trans, (E) and (Z) isomers thereof,and the pharmaceutically acceptable acid addition salts thereof when R¹and R² have one or more salt-forming basic amino components or when Aris pyridinyl and the hydrates thereof, with the proviso that when R³ ishydrogen, Z is oxygen, B is oxygen, and Ar is phenyl or phenylsubstituted by trifluoromethyl or aminocarbonyl, then R¹ and R² cannotbe a combination of hydrogen and loweralkyl, and the further provisothat when R³ is hydrogen, Z is oxygen, B is oxygen, and Ar is phenyl orphenyl substituted by fluoro, loweralkyl, loweralkoxy, trifluoromethyl,acetyl or aminocarbonyl, then R¹ and R² cannot both be hydrogen.

In the further definition of symbols in the formulas hereof and wherethey appear elsewhere throughout this specification and in the claims,the terms have the following significance.

The term "loweralkyl" as used herein, unless otherwise specified,includes straight and branched chain radicals of up to eight carbonsinclusive and is exemplified by such groups as methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyl,and octyl radicals, and the like. The term "loweralkoxy" has the formula--O--loweralkyl.

The term "cycloalkyl" as used herein includes primarily cyclic alkylradicals containing 3-9 carbon atoms inclusive and includes such groupsas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andthe like.

The term "loweralkylcycloalkyl" refers to cycloalkyl substituted byalkyl radicals of 1-8 carbon length.

The term "cycloalkylloweralkyl" refers to a cycloalkyl radical linkedvia 1-8 carbon alkyl chains, including branched chains, to the amidenitrogen.

The term "substituted allyl" means allyl substituted by alkyl radicalsin any one of its 3 positions.

The term "aryl" under the definition of R¹, R², and R³ refers to phenylor phenyl substituted by non-interfering radicals such as halo,loweralkyl, loweralkoxy, nitro, cyano, trifluoromethyl, carbomethoxy,carbethoxy, and the like.

The term "arylloweralkyl" under the definition of R¹, R², and R³ refersto an aryl group as defined above linked via 1-8 carbon alkyl chains,including branched chains, to the amide nitrogen.

The term "4-substituted-piperazinyl" under the definition of R¹ and R²refers to a piperazine radical substituted by radicals usually in thepharmaceutical art, including phenyl, halophenyl, loweralkoxyphenyl, 2,3 or 4-pyridinyl, 2, 4 or 5-pyrimidinyl, nitrophenyl,trifluoromethylphenyl, loweralkyl, phenylloweralkyl,loweralkoxycarbonyl, and the like.

The term "4-substituted homopiperazinyl" under the definition of R¹ andR² refers to a homopiperazinyl radical substituted by racicals usuallyin the pharmaceutical art, including phenyl, halophenyl,loweralkoxyphenyl, 2, 3 or 4-pyridinyl, 2, 4 or 5-pyrimidinyl,nitrophenyl, trifluoromethylphenyl, loweralkyl, phenylloweralkyl,loweralkoxycarbonyl, and the like.

The term "loweralkoxycarbonyl" under the definition of 4-substitutedpiperazinyl and 4-substituted homopiperazinyl has the formula--C(O)--O--loweralkyl.

As defined above under Formula I, pharmaceutically acceptable salts areincluded when R¹ or R² have one or more salt-forming amino components orwhen Ar is pyridyl. Salt-forming amino components are present, forexample, when either R¹ or R² are diloweralkylaminoloweralkyl or whenthey form piperazinyl or imidazolyl radicals or4-(2-pyridinyl)-1-piperazinyl. Pharmaceutically acceptable acid additionsalts are those salts which are physiologically compatible inwarm-blooded animals. The acid addition salts may be formed either bystrong or weak acids. Representative of useful strong acids arehydrochloric, hydrobromic, sulfuric and phosphoric acids. Representativeof useful weak acids are fumaric, maleic, succinic, oxalic, citric,tartaric, hexamic, and the like.

As stated above, the method of this invention employs the compounds ofFormula I to relieve muscle tension and spasticity (i.e., to relaxmuscle) and/or anxiety in animals, including humans. The procedure fortesting compounds for muscle relaxant activity is the Morphine-InducedStraub-Tail-In-Mice Test and the procedure for indicating antianxietyresponse is the Vogel Conflict Test based on shock suppressed drinkingbehavior. Both tests are given in detail hereinbelow under"Pharmacological Test Procedures."

The method utilizing one or more of the compounds of Formula I isadaptable for treating tensed and spastic muscles and for treatinganxiety in the same individual or for treating tensed and spasticmuscles when anxiety is not present or for treating anxiety when thereare no muscle problems. Examples of effective muscle treatment would befor muscular conditions arising from tetanus, whiplash, stroke, multipleschlerosis, cerebral palsy and the like.

Compounds of Formula I wherein R¹ and R² have an allyl, substitutedallyl, propargyl or cycloalkyl value are preferred for their potency asmuscle relaxants.

DETAILED DESCRIPTION OF THE INVENTION

The methods used to prepare the muscle relaxants and antianxiety agentsof Formula I which are used in the method of this invention areclassified as follows by equation under Method Classes A, B, and C.

Method Class A From Phenoxyazetidine ##STR5## Method Class B ViaAryloxy-(and Arylthio-)-1-chlorocarbonylazetidine (Ar=Phenyl,Substituted-phenyl, Pyridyl) ##STR6## Method Class C Via Methane (orPhenyl) sulfonyl azetidine ##STR7##

Method Class A reactions comprise a process for preparing phenoxycompounds of Formula I by reacting a compound of the formula: ##STR8##with one of the following classes of compounds: ##STR9##

Method Class B reactions comprise a process for preparing certainaryloxy and arylthio compounds of Formula I by reacting a compound ofthe formula: ##STR10## with one of the following classes of compounds:a) R¹ R² NH, or, b) a heterocyclic amino compound.

Method Class C reactions comprise a process for preparingm-fluorophenoxy compounds of Formula I by reacting a compound of theformula: ##STR11## with an isocyanate of the formula

    R.sup.2 --N═C═Z

to give a compound of the formula ##STR12## and thereafter reacting withsodium hydride and a metafluorophenol of the formula ##STR13## to give acompound of the formula ##STR14##

Methods of preparing the starting phenoxyazetidines used in Method ClassA are outlined by equation in Chart I. Methods of preparing the startingaryloxy (and arylthio)-1-carbonylazetidines used in Method Class B areoutlined by equation in Chart II.

The starting 1-(diphenylmethyl)-3-hydroxyazetidines may be prepared bythe method of Anderson & Lok., J. ORG. CHEM. (1972) 37: 3953 frombenzhydrylamine and an appropriate epihalohydrin. Cis and trans isomersare separated by chromatography when they exist. Startingα-methylbenzyl-3-azetidinol is prepared by the method of TetsuyaOkutani, et al., CHEM. PHARM. BULL. Vol. 22 (1974) p. 1490, and by themethod analogous to the above Anderson et al. method for1-(diphenylmethyl)-3-azetidinol. Preparations 1-26 illustrate themethods.

Chart I Preparation of Starting 1-Unsubstituted phenoxyazetidines##STR15## Chart II Preparation of Starting 1-Carbonyl-3-aryloxy (andarylthio) azetidines ##STR16## Chart III Preparation of StartingMethane-(or phenyl)-sulfonylazetidine ##STR17##

The novel process for the preparation of the chemical intermediateshaving the formula: ##STR18## wherein; B and Z are selected from oxygenor sulfur and may be the same or different;

Ar is selected from pyridyl in any of its positions optionallysubstituted by halogen, from phenyl or phenyl substituted by 1 or 2radicals selected from chloro, bromo, iodo, fluoro, loweralkyl,loweralkoxy, nitro, aminocarbonyl, or trifluoromethyl;

R³ is selected from hydrogen, loweralkyl, aryl or arylloweralkyl;

is comprised of reaction phosgene or thiophosgene in a suitable solventwith a compound having the formula: ##STR19## wherein; B is oxygen orsulfur;

R⁴ is loweralkyl, phenyl or phenyl substituted by a non-interferingradical;

X is hydrogen or a non-interfering radical, and

Ar is as defined above.

The process is illustrated further in Preparations 15-19, 26 and 27, andin the first parts of Examples 34-36 and 125. A preferred solvent ismethylene chloride, and the reaction is carried out at about 15°-45° C.,preferably at about 25° C. The product may be isolated by conventionalmeans or the solution containing the product may be subjected to otherreactants such as an amine. As will be recognized by one skilled in theart, the ##STR20## group or R⁴ when it is phenyl or substituted phenylmay be substituted by any radical which is economically feasible toprepare and does not react with phosgene (i.e., non-interfering group).Unsubstituted phenyl or phenyl substituted by common groups such aschloro, bromo, loweralkyl, loweralkoxy, nitro and the like arepreferred.

The following preparations illustrate synthesis of chemicalintermediates.

Preparation 1 trans-1-(Diphenylmethyl)-2-methyl-3-azetidinol oxalate[1:1]

A mixture of 126.4 g (0.72 mole) of diphenylmethylamine and 100 g (0.66mole) of 3-bromo-1,2-epoxybutane in 300 ml of methanol was stirred whilebeing protected from light for 96 hr, then heated at reflux for 30 hr asthe color changed from pale yellow to deep amber. A sample was assayedby ¹ H-nmr and showed 3 methyl doublets. A fine beige precipitate wasremoved by filtration (diphenylmethylamine hydrobromide) and thefiltrate concentrated on a rotary evaporator to yield 174.6 g of crudeoil. A 1.5 g sample was neutralized and placed on a 4 mm thick plate ofa Chromatotron® and eluted with 10% ethyl acetate-toluene. A total ofsixteen fractions were collected which consisted of 6 distinct spots byTLC. The major component separated was 700 mg and appeared to be thetrans isomer. This sample was converted to the oxalate salt. The mainconcentrate was converted to the free base with ammonium hydroxide andextracted into toluene which was dried over magnesium sulfate andconcentrated. The reaction residue was dissolved in methanol and treatedwith 58 g of oxalic acid, heated to give a homogenous solution andallowed to cool after seeding with a sample of the trans oxalate salt.Filtration yielded 62 g of white granular product, m.p. 147°-148.5° C. Asecond crop of 26 g was also obtained. The ¹ H-nmr spectrum showed onlya single CH₃ doublet with j (CH₃ -H) of 6.1 Hz which is consistent withthe trans compound.* Total yield of title compound was 88 g (38.8%).

Analysis: Calculated for C₁₇ H₁₉ NO.C₂ H₂ O₄ : C,66.46; H,6.16; N,4.08

Found: C,66.38; H,6.16; N,4.07

Preparation 2 1-(Diphenylmethyl)-3-azetidinol methanesulfonate (ester)hydrochloride [1:1]

A mixture of 60.02 g (0.22 mole) of 1-diphenylmethyl-3-azetidinolhydrochloride (prepared by the Method of Anderson and Lok, J. Org.Chem., 37: 3953 (1972)) and 48.94 g (0.484 mole) of triethylamine in 800ml of toluene was stirred for 24 hr, then cooled to 5° C. in an ice bathand treated with 27.7 g (0.24 mole) of methanesulfonyl chloride added ata rate which maintained the temperature below 15° C. The reactionmixture was stirred for 3 hr and filtered to remove the triethylaminehydrochloride. The filtrate was treated with 40 g (0.242 mole) of4-trifluoromethylphenol followed by 19.35 g (0.484 mole) of sodiumhydroxide and 1.6 g (0.005 mole) of tetrabutylammonium bromide in 60 mlof water. The reaction mixture was stirred rapidly at reflux for 18 hr,then stirred for 72 hr while it cooled to ambient temperature. Thereaction mixture was transferred to a separatory funnel and washed with4×200 ml of water (emulsion). The toluene phase was dried over magnesiumsulfate and concentrated in vacuo to 82 g of oil. This residue wasdissolved in 200 ml of isopropyl alcohol and treated with 20 ml ofconcentrated hydrochloric acid. Upon cooling, a solid separated and wasremoved by filtration (5.1 g). The filtrate was treated with isopropylether to give an oil which was worked up later. The solid was identifiedby spectral analysis as the methylsulfonate of the starting azetidinol.Recrystallization from isopropyl alcohol gave 3.3 g of fine whitecrystalline material, m.p. 172°-173° C., (shrinks 167° C.).

Analysis: Calculated for C₁₇ H₁₉ NO₃ S.HCl: C,57.70; H,5.70; N,3.96

Found: C,57.80; H,5.86; N,3.92

Preparation 3 trans-1-(Diphenylmethyl)-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine oxalate [1:1]

A stirred slurry of 1.2 g (0.03 mole) of sodium hydride (60% dispersionin mineral oil) in 50 ml of dry DMF was treated with 3.45 g (0.01 mole)of trans-1-diphenylmethyl-2-methylazetidin-3-ol oxalate added in smallportions. When the addition was complete and the evolution of hydrogenceased, the reaction was heated to 80° C. for 2 hr then 1.64 g (0.01mole) of 3-fluoro-trifluoromethylbenzene was added dropwise. Thereaction mixture was stirred at 80° C. for an additional 18 hr. Thereaction mixture was diluted with ice water and extracted with 3×25 mlof toluene. The extracts were combined, dried over magnesium sulfate,filtered, and the filtrate treated with 1 g of oxalic acid. Theresulting solid was collected by filtration. Recrystallization fromacetone-isopropyl ether yielded 2.2 g (4.5%) of fine white crystals,m.p. 146°-147° C. Proton NMR shows it to be the trans compound.

Analysis: Calculated for C₂₄ H₂₂ F₃ NO.C₂ H₂ O₄ : C,64.06; H,4.96;N,2.87

Found: C,64.26; H,4.99; N,2.89

Preparation 4 trans-2-Methyl-3-[3-(trifluoromethyl)phenoxy]azetidineoxalate [1:1]

A methanol-warm water solution of 33 g (0.068 mole) oftrans-1-diphenylmethyl-2-methyl-3-[3-(trifluoromethyl) phenoxy]azetidineoxalate was treated with ammonium hydroxide until basic, then extractedwith 4×150 ml of methylene chloride. The combined methylene chlorideextracts were washed with water, dried over magnesium sulfate, andconcentrated in vacuo to a pale yellow oil. This oil was dissolved in200 ml of 190 ethanol plus 5 ml of triethylamine and hydrogenated on aParr apparatus with 3.3 g of 5% palladium-on-charcoal catalyst with a 40psi atmosphere of hydrogen at 70° C. for 12 hr. After the calculatedamount of hydrogen had been absorbed, the catalyst was removed byfiltration and the filtrate concentrated in vacuo to yield 26.73 g ofcrude product. An 8 g portion was converted to the oxalate salt inisopropyl alcohol yielding 6.1 g of fine white powder; m.p. 155°-156° C.Total yield extrapolated from the aliquot converted to the oxalate saltwas 84% of theory.

Analysis: Calculated for C₁₁ H₁₂ F₃ NO.C₂ H₂ O₄ : C,48.61; H,4.39;N,4.36

Found: C,48.67; H,4.38; N,4.34

Preparation 5 trans-1-(Diphenylmethyl)-2-methyl-3-azetidinolmethanesulfonate (ester) hydrochloride [1:1]

A solution of 6 g (0.025 mole) oftrans-1-diphenylmethyl-2-methylazetidin-3-ol (obtained from thehydrochloride salt by partitioning in organic solvent and aqueous base,separating and evaporating the organic phase) in 40 ml of dry benzenewas treated with 10 ml of triethylamine and cooled to 5° C. Whilestirring, the reaction mixture was treated with 3.54 g (0.03 mole) ofmethanesulfonyl chloride at a rate to control the temperature below 10°C. After stirring for 3 hr, TLC (20% ethyl acetate/methylene chloride onsilica gel) showed the reaction to be incomplete. An additional 1.14 g(0.01 mole) of methanesulfonyl chloride was added and stirring continuedfor 1 hr. The reaction mixture was diluted with 100 ml of water and thebenzene layer separated, washed with 300 ml of water, dried overmagnesium sulfate and concentrated to an oil. The oil was dissolved inisopropyl ether and treated with ethereal hydrogen chloride. The solidsalt was removed and recrystallized from 190 ethanol to give 3.4 g (37%)of fluffy white crystals, m.p. 152°-153° C.

Analysis: Calculated for C₁₈ H₂₁ NO₃ S.HCl: C,58.77; H,6.03; N,3.81

Found: C,58.68; H,6.08; N,3.80

Preparation 6 1-(Diphenylmethyl)-3-[3-(trifluoromethyl)phenoxy]azetidine

N-Diphenylmethyl-3-hydroxyazetidine hydrochloride (I) was prepared frombenzhydrylamine and epichlorohydrin according to Anderson and Lok, J.Org. Chem., 37:3953 (1972). I (41.33 g, 0.15 mole) and triethylamine (42ml, 0.30 mole) were stirred in toluene (250 ml) while methanesulfonylchloride (12 ml, 0.15 m) was added dropwise over 10 minutes withstirring and the temperature was maintained between 4° and 12° C. TLC(silica gel, 10% ethyl acetate in methylene chloride) at one hour showedall starting materials had reacted. The mixture was filtered to removethe triethylamine hydrochloride which was rinsed twice with toluene. Thefiltrate and washings combined to about 450 ml of solution. To thissolution was added m-trifluoromethylphenol (27.5 g, 0.17 mole),tetrabutyl ammonium bromide (2.4 g), 50% sodium hydroxide (24 g, 0.3mole) and water (24 ml) and the mixture was stirred vigorously andheated to reflux under nitrogen for 2.5 hr. The toluene layer of themixture was separated and washed once with water, dried over sodiumsulfate and evaporated to an oil. This oil was seeded and pumped on anoil pump overnight. A solid cake weighing 49.7 was obtained. Some ofthis solid was dissolved in isopropanol with brief heating. Water wasthen added to cause slight cloudiness. The mixture was seeded and cooledto cause crystallization. The white solid was collected by filtration,washed with 50% aquous isopropanol, and dried under vacuum overnight.Proton NMR showed slight contamination by silicone oil, m.p. 82.5°-84°C.

Analysis: Calculated for C₂₃ H₂₀ F₃ NO: C,72.05; H,5.26; N,3.65

Found: C,71.62; H,5.29; N,3.61

Preparation 7 3-(3-Fluorophenoxy)azetidine oxalate [1:1]

A mixture of 55.1 g (0.2 mole) of 1-diphenylmethyl-3-azetidinolhydrochloride [1:1] (prepared by the Method of Andersen and Lok, J. Org.Chem. 37: 3953 (1972)) and 50.5 g (0.5 mole) of triethylamine in 1.2liters of toluene was stirred at ambient temperature under a nitrogenatmosphere for 5 hr, then cooled to 5° C. in an ice water bath andmethanesulfonyl chloride added dropwise with stirring. The reactionmixture was allowed to warm to ambient temperature while stirring forapproximately 18 hr.

The reaction mixture was diluted with 600 ml of isopropyl ether and thesolid removed by filtration. The filtrate was then treated with 22.5 g(0.2 mole) of 3-fluorophenol and 24 g (0.6 mole) of sodium in 50 ml ofwater. Tetrabutylammonium bromide, 1 gm, was added to the reactionmixture and the reaction mixture was stirred rapidly and heated atreflux for approximately 16 hr.

The toluene layer was separated and washed with water twice (200 ml×2).Then while stirring, 20 g (0.22 mole) of oxalic acid was added as asolution in 100 ml of isopropyl alcohol and the mixture was allowed tostir for approximately 16 hr. Filtration yielded 61.6 g of whitegranular solid 1-diphenylmethyl-3-(3-fluorophenoxy)azetidine oxalate.

A slurry of 55 g of this white granular solid in 350 ml of ethanol wastreated with 5.5 g (10% w/w) of 20% palladium hydroxide on carbon undernitrogen atmosphere and hydrogenated on a Parr apparatus at 70° C. withan initial hydrogen pressure of 45 psi for 18 hr. The hydrogen uptakecould not be obtained since some leakage had occurred. The product wasan insoluble solid which had to be converted to the free base in warmwater with potassium carbonate. This mixture was stirred with chloroformand then filtered through Celite® to remove the catalyst. The chloroformportion was separated and the aqueous basic solution extracted with 400ml of chloroform. The chloroform portions were combined, dried overmagnesium sulfate and concentrated on a rotary evaporator to yield 36.45g of oil. The oil was dissolved in ethanol and treated with 10 g ofoxalic acid, yielding 15.5 g (46.4%) of crude title compound. A samplewas recrystallized from ethanol, m.p. 170°-171° C.

Analysis: Calculated for C₉ H₁₀ FNO.C₂ H₂ O: C,51.37; H,4.70; N,5.45

Found: C,51.41; H,4.72; N,5.47

Preparation 8 1-(Diphenylmethyl)-3-(4-fluorophenoxy)azetidine oxalate[1:1]

A slurry of 22 g (0.55 mole) of sodium hydride (60% in mineral oil) in200 ml of dry dimethylformamide was stirred at 50° C. under nitrogenatmosphere and treated with 119.7 g (0.5 mole) of1-diphenylmethyl-3-azetidinol in 360 ml of dry dimethylformamide at arate which maintained a steady evolution of hydrogen and maintained atemperature between 70°-80° C. After the addition was complete, thereaction mixture was heated to 90° C. and stirred for 1 hr then treatedwith 59.9 g (0.55 mole) of 1,4-difluorobenzene and stirred at 90° C. foran additional 32 hr. After cooling to ambient temperature, the reactionmixture was diluted with 4 liters of water and extracted with 4×1000 mlof toluene.* The toluene extracts were combined, dried over magnesiumsulfate and concentrated in vacuo, yielding 155.9 g of amber oil. Asecond extraction with 4×200 ml of methylene chloride yielded, afterconcentration, an additional 20 g of yellow oil. These oils werecombined, dissolved in 1 liter of 60% ethyl acetate/toluene, thentreated with 150 g of silica gel and stirred for 3 hr. This mixture wasfiltered and the silica gel washed with 500 ml of 60% ethylacetate/toluene. The combined effluents were treated with 45.5 g ofoxalic acid (0.5 mole) and stirred for 18 hr. The solvent was decantedfrom the partially crystalline residue. This crude residue wasrecrystallized from isopropanol to yield 149.3 g (70.1%) of product asthe oxalate salt. A sample was recrystallized for elemental analysisfrom ethanol, m.p. 162°-163° C.

Analysis: Calculated for C₂₂ H₂₀ FNO.C₂ H₂ O₄ C,68.08; H,5.24; N,3.31

Found C,67.96; H,5.33; N,3.32

Preparation 9 3-(3,4-Dichlorophenoxy)-1-(diphenylmethyl)azetidine

A mixture of 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol and 22 g(0.22 mole) of triethylamine in 800 ml of toluene was stirred in a waterbath while 27.5 g (0.22 mole) of methanesulfonyl chloride was addeddropwise and stirring was continued for 18 hr. The reaction mixture wastreated with 400 ml of isopropyl ether then filtered. The filter cakewas washed with 2×150 ml of 50/50 isopropyl ether and toluene. Thecombined filtrates were treated with 32.6 g (0.2 mole) of3,4-dichlorophenol, 100 mg of tetrabutylammonium bromide and 24 g (0.6mole) of sodium hydroxide in 100 ml of water. This mixture was stirredvigorously at reflux for 16 hr. The basic aqueous portion was separatedand the organic portion washed with water, dried over magnesium sulfatethen concentrated to a solid residue, 74.5 g. Several recrystallizationsfrom ethanol-water gave a product which was contaminated with startingazetidinol. Therefore, the material, 57.4 g, was dissolved in tolueneand treated with silica gel. After stirring for 6 hr, the silica gel wasremoved by filtration and washed with 50/50 ethyl acetate and toluene.The filtratrs were concentrated to yield 45.9 g (59.7%) of pure product.A sample for elemental analysis was recrystallized from ethanol, m.p.114°-115° C.

Analysis: Calculated for C₂₂ H₁₉ Cl₂ NO: C,68.76; H,4.98; N,3.65

Found: C,68.73; H,5.00; N,3.65

Preparation 10 3-(4-Chlorophenoxy)-1-(diphenylmethyl)azetidine

A stirred slurry of 41.3 g (1.03 mole) of 60% sodium hydride (in mineraloil) in 500 ml of dry dimethylformamide under nitrogen atmosphere washeated to 50° C. and 22.5 g (0.94 mole) of 1-diphenylmethyl-3-azetidinolin 700 ml of dry dimethylformamide was added dropwise at a rate whichmaintained the temperature between 70°-80° C. and allowed a gentleevolution of hydrogen. After the addition was complete, the reactionmixture was stirred for 2 hr at 90° C., then 125 g (0.94 mole) of1-chloro-4-fluorobenzene was added dropwise. The reaction mixture wasstirred at 90° C. under nitrogen for 24 hr, then stirred an additional24 hr while the reaction mixture cooled to ambient temperature. Thereaction mixture was poured into 6 liter of ice water and the solidwhich formed was collected by filtration to yield 271 g of wet crudeproduct. A sample was recrystallized for elemental analysis fromethanol, yielding a fine tan crystalline product in 82.4% yield, m.p.113°-114° C.

Analysis: Calculated for C₂₂ H₂₀ ClNO: C,75.53; H,5.76; N,4.00

Found: C,75.58; H,5.72; N,3.97

Preparation 11 3-(3-Bromophenoxy)-1-(diphenylmethyl)azetidine oxalate[1:1]

A stirred slurry of 13.2 g (0.33 mole) of sodium hydride (60% dispersionin mineral oil) in 100 ml of dry dimethylformamide under nitrogenatmosphere was heated to 50° C. and 71.8 g (0.3 mole) of1-diphenylmethyl-3-azetidinol in 300 ml of dry dimethylformamide wasadded at a rate which maintained the temperature between 70°-80° C. anda steady evolution of hydrogen. After the addition, the reaction mixturewas stirred at 90° C. for 2 hr, then 57.8 g (0.315 mole) of3-bromofluorobenzene was added all at once. The reaction mixture becameexothermic as the temperature quickly reached 133° C. The reactionmixture was stirred for 4 hr as it cooled to 90° C. then heated at 90°C. for 12 hr and allowed to cool for the next 34 hr. The reactionmixture was poured into ice water and the oil which separated wasextracted into 800 ml of toluene. The aqueous phase was extracted with3×500 ml of toluene and the toluene extracts were combined, washed with100 ml of water, and dried over magnesium sulfate and filtered. Thefiltrate was treated with 27 g of oxalic acid in 100 ml of isopropanoland stirred for 24 hr. Since no solid salt formed, the mixture wasconcentrated in vacuo and the amber residue washed with petroleum etherto remove mineral oil. Upon standing, the 109 g of amber oil solidified.A sample was recrystallized from absolute ethanol, yielding finecotton-like white crystals, m.p. 146°-147° C.

Analysis: Calculated for C₂₂ H₂₀ BrNO.C₂ H₂ O₄ : C,59.52; H,4.58; N,2.89

Found: C,59.33; H,4.65; N,3.00

*The main bulk of the material had approximately 20% of startingazetidinol present. The mixture of salts was converted to the free baseand treated with 200 g of silica gel in toluene. The silica gel wasremoved by filtration and washed with 500 ml of 50/50 toluene/ethylacetate. The filtration yielded, upon concentration, 59.4 g (63.3%) ofyellow oil which contained a trace of starting azetidinol by TLC.

Preparation 12 1-(Diphenylmethyl)-3-(3-methoxyphenoxy)azetidine oxalate[1:1]

A stirred mixture of 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinoland 22 g (0.22 mole) of triethylamine in 800 ml of toluene was cooled ina water bath while 27.5 g (0.22 mole) of methanesulfonyl chloride wasadded dropwise. After stirring for 18 hr, the reaction mixture wastreated with 200 ml of water to dissolve the triethylaminehydrochloride. The toluene portion was separated and washed with 2×200ml of water and added to a solution of 24 g (0.6 mole) of sodiumhydroxide in 100 ml of water. This mixture was stirred vigorously while25 g (0.2 mole) of 3-methoxyphenol was added along with 100 ml oftetrabutylammonium bromide and then heated at reflux for 72 hr. After anadditional 48 hr of stirring without heat, the basic portion wasseparated and the toluene portion washed with 3×100 ml of water, driedover magnesium sulfate, then concentrated in vacuo (64 g). Thin layerchromatography (20% ethyl acetate-toluene on silica gel) showedapproximately 30% starting azetidinol present. The crude material wasplaced on a 1200 g silica gel column and eluted with toluene until thematerial at the solvent front came off the column. The elution solventwas changed to an ethyl acetate-toluene gradient ranging from 2-40%ethyl acetate. Most of the material came off between 5-20% ethylacetate. A total of nine fractions were shown to be usable by TLC andcombined and concentrated in vacuo, to give 49.64 g of oil (71.8%). Aportion of this oil was converted to the oxalate salt in acetoneisopropyl ether and recrystallized from methylisobutyl ketone, yieldingfine white crystals, m.p. 133°-134° C.

Analysis: Calculated for C₂₃ H₂₃ NO₂.C₂ H₂ O₄ : C,68.95; H,5.78; N,3.22

Found: C,68.81; H,5.80; N,3.19

Preparation 13 3-(4-Bromophenoxy)-1-(diphenylmethyl)azetidine

A stirred slurry of 8.8 g (0.22 mole) of 60% sodium hydride (mineral oilsuspension) in 200 ml of dry dimethylformamide was heated under nitrogenatmosphere to 70° C. then 48 g (0.2 mole) of1-diphenylmethyl-3-azetidinol in 150 ml of dry dimethylformamide wasadded dropwise at a rate which maintained the temperature below 90° C.and allowed a steady hydrogen evolution. The reaction mixture wasstirred for 1 hr at 90° C., treated with 38.5 g (0.22 mole) of4-bromofluorobenzene and heated at 90° C. for 36 hr. The reactionmixture was diluted with 1200 ml of water and after stirring for 3 hr,the solid precipitate was collected by filtration to yield 112 g ofcrude, wet product. Recrystallization from ligroin yielded 65.6 g(83.2%) of white crystals, m.p. 116°-117° C.

Analysis: Calculated for C₂₂ H₂₀ BrNO: C,67.01; H,5.11; N,3.55

Found: C,67.13; H,5.12; N,3.55

Preparation 14 1-(Diphenylmethyl)-3-(3-methylphenoxy)azetidine

A stirred mixture of 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinoland 22 g (0.22 mole) of triethylamine in 800 ml of toluene undernitrogen was cooled in a water bath while 27.5 g (0.22 mole) ofmethanesulfonyl chloride was added dropwise. After stirring for 20 hr,the reaction mixture was treated with 200 ml of water to dissolve thetriethylamine hydrochloride. The aqueous phase was separated and thetoluene phase was washed with 2×100 ml water. The toluene solution wasadded to a mixture of 22.8 g (0.2 mole) of 3-methylphenol (95%), 24 g(0.6 mole) of sodium hydroxide and 100 mg of tetrabutylammonium bromidein 100 ml of water and the mixture was heated at reflux and stirredvigorously for 42 hr.

The reaction mixture was cooled to ambient temperature and the basicphase separated. The toluene phase was washed with 3×100 ml of water,dried over magnesium sulfate and concentrated in vacuo to yield an amberresidue, 89.7 g. The residue was dissolved in 100 ml of toluene, placedon a 900 g silica gel column and eluted with toluene until productappeared, the elution solvent was changed to 10% ethyl acetate intoluene and elution continued until no more product was detected.Fractions containing product were combined and concentrated in vacuo toyield 30.55 g of pale yellow oil, which slowly solidified on standingand was recrystallized from hexane at freezer temperature to yield 19.8g (30.1%) of fine white crystals, m.p. 68°-70° C.

Analysis: Calculated for C₂₃ H₂₃ NO: C,83.86; H,7.04; N,4.25

Found: C,84.14; H,7.00; N,4.25

Preparation 15 3-(4-Chlorophenoxy)-1-azetidinecarbonyl chloride

A solution of 32.34 g (0.33 mole) of phosgene in 200 ml of methylenechloride cooled with a tap water bath was treated with 45.5 g (0.33mole) of potassium carbonate and stirred for 30 min, then 105 g (0.3mole) of 3-(4-chlorophenoxy)-1-diphenylmethylazetidine in 600 ml ofmethylene chloride was added dropwise. After stirring for an additional18 hr, the reaction mixture was filtered to remove the inorganic saltsthen concentrated in vacuo to a dark oily residue, 127.7 g. A solidformed upon standing which was triturated with boiling 30/60 petroleumether 3 times to remove diphenylmethyl chloride. The residue, 33 g ofdark brown crystalline material, was mainly starting materia. Uponstanding, a white crystalline material separated from the petroleumether triturates (4.4 g, m.p. 78°-80° C.). The triturates wereconcentrated in vacuo, yielding 31 g of pale yellow tacky crystals.Trituration of these crystals with isopropyl ether yielded 21.9 g(35.6%) of pale yellow crystalline product.

Analysis: Calculated for C₁₀ H₉ Cl₂ NO₂ : C,48.81; H,3.69; N,5.69

Found: C,49.10; H,3.61; N,5.63

Preparation 16 3-(3-Bromophenoxy)-1-azetidinecarbonyl chloride

A solution of 22.7 g (0.23 mole) of phosgene in 200 ml of methylenechloride was treated with 29 g (0.23 mole) of potassium carbonate,stirred for 30 min, then 75.4 g (0.19 mole) of3-(3-bromophenoxy)-1-diphenylmethylazetidine in 150 ml of methylenechloride was added dropwise. After stirring for 5 hr, the inorganicsalts were removed by filtration and the filtrate was washed with waterto destroy excess phosgene. Concentration (after drying) in vacuoyielded 96.85 g of oily residue. Trituration of the residue withisopropyl ether yielded 42 g of crude tan-gray product. A sample foranalysis was recrystallized from isopropyl ether, m.p. 87°-88° C.

Analysis: Calculated for C₁₀ H₉ BrClNO₂ : C,41.34; H,3.12; N,4.82

Found: C,41.12; H,3.14; N,4.78

Preparation 17 3-(4-Bromophenoxy)-1-azetidinecarbonyl chloride

A stirred solution of 18.8 g (0.192 mole) of phosgene in 100 ml ofmethylene chloride was cooled to 15° C. in a water bath, then treatedwith 26.5 g (0.192 mole) of potassium carbonate. After stirring for 30min, 63 g (0.16 mole) of 3-(4-bromophenoxy)-1-diphenylmethylazetidine in180 ml of methylene chloride was added dropwise and stirring continuedfor 18 hr. The reaction mixture was diluted with ice water to dissolvethe inorganic salts, the aqueous portion was separated and the organicphase washed with 25 ml of ice water. After separation, the methylenechloride solution was dried with magnesium sulfate, then concentrated invacuo to a viscous yellow oil. Trituration of the residue with 30/60petroleum ether yielded a crystalline product, 76.9 g, which wasrecrystallized from isopropyl ether-ligroin (50-50) to yield 34.8 g(74.8%) of white granular crystals, m.p. 77°-78° C.

Analysis: Calculated for C₁₀ H₉ BrClNO₂ : C,41.34; H,3.12; N,4.82

Found: C,41.32; H,3.11; N,4.80

Preparation 18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride

A solution of 14 g (0.144 mole) of phosgene in 200 ml of methylenechloride was treated with 19.9 g (0.144 mole) of anhydrous potassiumcarbonate and stirred for 1 hr, then 45.9 g (0.12 mole) of1-diphenylmethyl-3-(3,4-dichlorophenoxy)azetidine in 100 ml of methylenechloride was added dropwise and stirring was continued for 72 hr. Thereaction mixture was filtered to remove the inorganic salts and thenconcentrated in vacuo to a pale yellow oil (67 g). Trituration of theresidue with cyclohexane yielded a crude pale yellow solid (23.6 g). Thefiltrate was treated with ligroin and upon standing, an additional 13.3g of tacky material was obtained. After several recrystallizations fromcyclohexane to remove traces of diphenylmethyl chloride a portion wasobtained as fine white crystals, in 70.1% yield, m.p. 96°-99° C.

Analysis: Calculated for C₁₀ H₁₈ Cl₃ NO₂ : C,42.81; H,2.87; N,4.99

Found: C,43.32; H,2.89; N,4.99

Preparation 19 3-(4-Fluorophenoxy)-1-azetidinecarbonyl chloride

A solution of 52.09 g (0.527 mole) of phosgene in 500 ml of methylenechloride was stirred with 73 g (0.53 mole) of potassium carbonate undernitrogen atmosphere for 30 min, then treated with 146.3 g (0.439 mole)of 1-diphenylmethyl-3-(4-fluorophenoxy)azetidine in 300 ml of methylenechloride added dropwise. After stirring for 18 hr, the reaction mixturewas treated with 200 ml of water added slowly. The aqueous phase wasseparated and the organic solution dried by filtration through Whatmanphase separating filter paper then concentrated in vacuo to a pale amberoil. Trituration of the oil with 30/60 petroleum ether yield a crudetacky solid, 89.3 g (88.6%). A portion of this solid was recrystallizedfrom 30/60 petroleum ether yielding a fine white crystalline product,m.p. 44°-52° C. A second recrystallization from isopropyl ether yieldedfine white crystals, m.p. 57°-58.5° C.

Analysis: Calculated for C₁₀ H₉ ClFNO₂ : C,52.30; H,3.95; N,6.10

Found: C,52.42; H,3.91; N,6.08

Preparation 20 3-Phenoxyazetidine oxalate

The title compound is prepared by a procedure similar to that used inExample 1 of U.S. Pat. No. 4,379,151 to produce3-phenoxyazetidinemethanesulfate. A solution of1-diphenylmethyl-3-phenoxyazetidine in ethanol is treated with 20%palladium hydroxide on carbon and hydrogenated for approximately 24 hrat about 45 psi and 80° C. The mixture is filtered and filtrateconcentrated. The residue is diluted with ethanol and treated withoxalic acid, and the title compound recrystallized from methanol.

Preparation 21 1-(1-Phenylethyl)-3-azetidinol maleate [1:1]

A solution of 60.59 g (0.5 mole) of α-phenethylamine and 46.27 g (0.5mole) of epichlorohydrin in 200 ml of methanol was allowed to standprotected from light for 96 hr. The reaction mixture was then stirred atreflux for 72 hr and the solvent removed in vacuo. Trituration of theoil residue with isopropyl ether gave some white crystalline product(α-phenethylamine hydrochloride) which was removed by filtration. Thecrude product solution was converted to the free base by adding ammoniumhydroxide and extracting with 4×200 ml of toluene. The toluene extractswere combined, dried over magnesium sulfate and filtered. The filtratewas treated with 58 g of maleic acid dissolved in 800 ml ofmethylisobutyl ketone. The crude product was collected in 3 fractions toyield a total of 62 g of maleate salt (42.4%). A sample wasrecrystallized from ethyl acetate for analysis purposes, m.p. 113°-114°C.

Analysis: Calculated for C₁₁ H₁₅ NO.C₄ H₄ O₄ : C,61.42; H,6.53 N,4.78

Found: C,61.37; H,6.65; N,4.80

Preparation 22 2-[1-(1-Phenylethyl)-3-azetidinyloxy]pyridine

The maleate salt of 1-(1-phenylethyl)-3-azetidinol (65 g, 0.22 mole) waspartitioned between toluene and dilute sodium hydroxide and wasextracted once with toluene. The organic layer was dried (sodiumsulfate) and concentrated. The residue was dissolved in 125 ml ofdimethylformamide and added dropwise to a stirred suspension of 9.6 g(0.24 mole) of sodium hydride (washed three times with isooctane) in 400ml of dimethylformamide at 25°-35° C. The solution was heated to 65° C.and 35 g (0.22 mole) of 2-bromopyridine was added dropwise while heatingto 75° C. The solution was stirred and heated at 90° C. for 1 hrfollowed by heating at 120° C. for 2.75 hr. The mixture was stirred atroom temperature overnight and concentrated. The residue was partitionedbetween water and isopropyl ether. The organic layer was washed twicewith water, dried (sodium sulfate), filtered and concentrated. Crudeyield was 30 g. The residue was distilled to give 8 g of product, bp128°-134° C./0.01 mm.

Analysis: Calculated for C₁₆ H₁₈ N₂ O: C,75.57; H,7.13; N,11.01

Found: C,75.20; H,7.18; N,10.90

Preparation 23 3-(3-Methoxyphenoxy)-1-azetidinecarbonyl chloride

Utilizing the procedure of Preparation 15 and reacting the following insequence:

phosgene,

potassium carbonate, and

1-diphenylmethyl-3-(3-methoxyphenoxy)azetidine

(free base obtained in Preparation 12), the title compound is obtained.

Preparation 24 3-(3-Methylphenoxy)-1-azetidinecarbonyl chloride

Utilizing the procedure of Preparation 15 and reacting the following insequence:

phosgene,

potassium carbonate, and

1-diphenylmethyl-3-(3-methylphenoxy)azetidine

(free base obtained in Preparation 14), the title compound is obtained.

Preparation 25 3-[(4-Chlorophenyl)thio]-1-(diphenylmethyl)azetidine

A stirred mixture of 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol,and 22 g (28 ml) (0.22 mole) of triethylamine in 800 ml of toluene undernitrogen was cooled in a water bath then treated with 27.5 g (0.22 mole)of methanesulfonyl chloride added dropwise. After stirring for 16 hr,the reaction mixture was diluted by adding 200 ml of isopropyl ether.The triethylamine hydrochloride was removed by filtration and washedwith 200 ml of (50/50) toluene/isopropyl ether. The filtrates werecombined, washed with 2×200 ml of water and returned to the reactionmixture. The reaction mixture was treated with 24 g (0.6 mole) of sodiumhydroxide in 100 ml of water, 6.5 g (0.02 mole) of tetrabutylammoniumbromide and 31.8 g (0.22 mole) of 4-chlorothiophenol then heated atreflux while stirring vigorously. After 96 hr, TLC showed the expectedproduct to be approximately 80% of the reaction mixture. After cooling,the organic phase was separated, washed with water (3×200 ml) andtreated with 25 g of oxalic acid dihydrate in 100 ml of methanol. Theprecipitated product was collected by filtration, yielding 75 g of crudeoxalate salt. The oxalate salt was suspended in warm water and treatedwith 0.4 mole (26 g) of potassium hydroxide. The solid whichprecipitated from the basic solution was collected and recrystallizedfrom methanol with charcoal treatment to yield 17.6 g of white granularcrystals, m.p. 84°-86° C. A second crop of crystals was obtained fromthe filtrate after standing (8.6 g). The yield was 36%.

Analysis: Calculated for C₂₂ H₂₀ ClNS: C,72.21; H,5.50; N,3.83

Found: C,72.17; H,5.53; N,3.89

Preparation 26 3-[(4-Chlorophenyl)thio]-1-azetidinecarbonyl chloride

A stirred mixture of 8.5 g (0.086 mole) of phosgene and 12 g (0.086mole) of potassium carbonate in 200 ml of methylene chloride was cooledin a water bath under nitrogen atmosphere while 26.3 g (0.072 mole) of3-[(4-chlorophenyl)thio]-1-diphenylmethylazetidine in 100 ml ofmethylene chloride was added dropwise. After the addition, the reactionmixture was stirred for 20 hr then treated with enough ice to form athick paste. The methylene chloride solution was decanted, filteredthrough Whatman phase separating paper and concentrated in vacuo. Theresidue (40 g) was triturated 3 times at -78° C. with 30/60 petroleumether and allowed to warm to 0° C. before decanting the petroleum ether.The fine granular solid which remained was collected by filtration toyield 14.1 g (75%) of crude product. A sample was recrystallized fromhexanes for analysis, m.p. 47°-48° C.

Analysis: Calculated for C₁₀ H₉ Cl₂ NOS: C,45.82; H,3.46; N,5.34

Found: C,45.78; H,3.40; N,5.37

Preparation 27 3-[3-(Trifluoromethyl)phenoxy]-1-azetidinecarbonylchloride

A solution of 35.6 g (0.36 mole) of phosgene in 200 ml of methylenechloride at 5° C. was stirred with 50 g (0.36 mole) of potassiumcarbonate for 1 hr. To the mixture was added dropwise 115 g (0.3 mole)of 1-diphenylmethyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 400 ml ofmethylene chloride. After stirring for 18 hr, the reaction mixture wasfiltered and the filtrate was washed with water, dried over magnesiumsulfate and concentrated on a rotary evaporator to a viscous oilresidue, 133.2 g. Trituration of the residue with hexane gave a solidwhich was recrystalized from cold hexane to yield 52 g (62%) of whitecrystals, m.p. 72.5°-74° C.

Analysis: Calculated for C₁₁ H₉ F₃ ClNO₂ : C,47.25; H,3.24; N,5.00

Found: C,47.63; H,3.25 N,5.12

Preparation 28 1-(Diphenylmethyl)-2-methyl-3-[3-(trifluoromethyl)phenoxy]acetidine cis isomer fumarate [1:1]

A stirred slurry of 4.4 g (0.11 mole) of a 60% mineral oil dispersion ofsodium hydride in 50 ml of dry dimethylformamide under nitrogenatmosphere was heated to 80° C. and treated with 25.3 g (0.1 mole) of1-diphenylmethyl-2-methyl-3-azetidinol, cis isomer in 100 ml of drydimethylformamide added dropwise at a rate that gave a smooth evolutionof hydrogen and maintained the temperature at 80°-85° C. After theaddition, the reaction mixture was stirred at 86°-88° C. for 2 hr, then18.1 g (0.11 mole) of 3-(trifluoromethyl)fluorobenzene was added all atonce (exothermic to 106° C.). After 3.5 hr, TLC (20% ethylacetate/toluene on silica gel) showed about 80% product had formed. Thereaction mixture was treated with 30% additional sodium hydride and 10%additional 3-(trifluoromethyl)fluorobenzene. The reaction mixture wasstirred an additional 7 hr at 86° C. and allowed to cool to ambienttemperature while stirring approximately 18 hr. The reaction mixture wasdiluted with water and extracted with benzene (4×200 ml). The combinedextracts were dried over magnesium sulfate then concentrated in vacuo(45.1 g). The crude product was chromatographed on a 1200 g silica gelcolumn by eluting with chloroform. The effluent fractions containingproduct were combined and concentrated in vacuo to yield 35.3 g ofproduct (88.9%). A sample was treated with fumaric acid and crystallizedfrom 2-propanol, m.p. 178°-180° C.

Analysis: Calculated for C₂₄ H₂₂ F₃ NO.C₄ H₄ O₄ : C,65.49; H,5.10;N,2.73

Found C,65.58; H,5.16; N,2.73

The following examples illustrate preparation of compounds encompassedby Formula I and useful in the method of treatment of the invention. Thestructure of the compounds in the examples are shown in Table 1. Thescope of the invention is not limited by the examples, however.

EXAMPLE 1N-Methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide

Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalyticdebenzylation of 26.0 g (0.078 mole) of1-benzhydryl-3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in100 ml of methylene chloride and treated dropwise under a nitrogenatmosphere with a solution of 5.0 g (0.0678 mole) of ofmethylisothiocyanate in 15 ml of methylene chloride. The reactionmixture was stirred for 16 hr at ambient temperature and let stand overthe weekend. The solution was filtered through a celite filter pad toremove a fine crystalline precipitate and the filtrate was evaporatedunder reduced pressure. The residual oil was crystallized from isopropylether to give 12.6 g of product, m.p. 79°-86° C. A 5.0 g sample wasrecrystallized from isopropyl ether (charcoal) to give 3.2 g, m.p.89°-93° C., which was shown by TLC on silica gel (10% methanol-toluene)to be contaminated by a lower R_(f) material. The filtrate wasevaporated under reduced pressure, combined with the 3.2 g of solid anddissolved in 100 ml of methylene chloride. The solution was stirred with25 g of silica gel for 0.5 hr and filtered through a sintered glassfilter. The silica gel was washed with a small volume of methylenechloride and the filtrate evaporated under reduced pressure. Theresidual solid was recrystallized from isopropyl ether to give 1.3 g ofpure product, m.p. 96°-98° C.

Analysis: Calculated for C₁₂ H₁₃ F₃ N₂ OS: C,49.65; H,4.51; N,9.65

Found: C,49.58; H,4.48; N,9.58

EXAMPLE 2N-(2,6-Dimethylphenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide

Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalyticdebenzylation of 30.0 g (0.078 mole) of1-benzhydryl-3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in100 ml of methylene chloride and treated dropwise under a nitrogenatmosphere with a solution of 12.7 g (0.078 mole) of2,6-dimethylphenylisothiocyanate in 25 ml of methylene chloride. Theproduct began to precipitate during the addition and an additional 50 mlof methylene chloride was added to facilitate stirring. After stirringovernight at ambient temperature, the product was collected byfiltration (13.5 g, m.p. 196°-199° C.) A 6.0 g sample was recrystallizedfrom isopropanol to give 5.3 g of product, m.p. 197°-199° C.

Analysis: Calculated for C₁₉ H₁₉ F₃ N₂ OS: C,59.99; H,5.03; N,7.36

Found: C,60.04; H,5.04; N,7.35

EXAMPLE 3N-(Phenylmethyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

To a stirred and chilled (10°-20° C.) solution of 0.04 mole of3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of methylene chloridewas added dropwise 6.12 g (0.046 mole) of benzyl isocyanate. Thereaction mixture was stirred at room temperature for 2 hr and wasfiltered. The filter cake was washed with petroleum ether (2×50 ml),dilute aqueous sodium bicarbonate (2×50 ml), and water (2×50 ml),yielding 12 g (86%). Recrystallization twice from ethyl acetate gave 9.0g of clear white flakes, m.p. 173.5°-175° C.

Analysis: Calculated for C₁₈ H₁₇ F₃ N₂ O₂ : C,61.71; H,4.89; N,8.00

Found: C,61.57; H,4.87; N,7.99

EXAMPLE 4N-(2,6-Dichlorophenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide

A solution of 0.04 mole of 3-[3-(trifluoromethyl) phenoxy]azetidine in100 ml of absolute ethanol was stirred in a tap water bath while 8.16 g(0.04 mole) of 2,6-dichlorophenyl isothiocyanate was added all at once.The reaction was slightly exothermic and as the isothiocyanate began todissolve, product began to precipitate. After stirring for 45 minutesthe reaction mixture was heated on a steam bath to assure that all theisothiocyanate dissolved, and upon cooling, filtration yielded 15.2 g ofwhite crystalline product. A portion of this material (7.9 g) wasrecrystallized from absolute ethanol to give 4.3 g of pure crystallinepowder, m.p. 196°-197° C.

Analysis: Calculated for C₁₇ H₁₃ F₃ Cl₂ N₂ OS: C,48.47; H,3.11; N,6.65

Found: C,48.40; H,3.07; N,6.54

EXAMPLE 5 N-[3-(Diethylamino)propyl]-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide, oxalate [1:1]

A solution of (0.0584 mole) of 3-[3-(trifluoromethyl) phenoxy]azetidinewas stirred at 10° C. while 10.66 g (0.0584 mole) of3-(diethylamino)propyl isothiocyanate was added all at once. Afterstirring overnight at ambient temperature, the reaction mixture wasconcentrated at 50° C. on a rotary evaporator to a thick syrup residue.The residue was dissolved in isopropanol and treated with 5.3 g ofoxalic acid, warmed on a steam bath to dissolve the acid, and uponcooling, a solid salt precipitated. An equal volume of isopropyl etherwas added to ensure complete precipitation. Filtration gave 26 g ofcrude product. A portion (13 g) was recrystallized fromisopropanol/methanol/isopropyl ether (100/50/50) (cooled in arefrigerator) to yield upon filtration 7.5 g of white product, m.p.155°-157° C. Proton NMR confirmed that this was the expected product.

Analysis: Calculated for C₁₈ H₂₆ F₃ N₃ O.C₂ H₂ O₄ : C,50.10; H,5.89N,8.76

Found: C,50.02; H,5.97; N, 8.89

EXAMPLE 6N-[3-(Dimethylamino)propyl]-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbothiomide

A stirred solution of 0.0584 mole of3-[3-(trifluoromethyl)phenoxy]azetidine at 10° C. was treated with 8.42g (0.0584 mole) of 3-(dimethylamino)propyl isothiocyanate all at onceand allowed to stir at ambient temperature overnight. The reactionmixture was treated with 5.3 g (0.0584 mole) of oxalic acid and dilutedwith 200 ml of isopropyl ether which yielded only 3.8 g of product. Thevolume was reduced to 100 ml at 50° C. in vacuo and diluted with 500 mlof isopropyl ether to yield an additional 15.3 g of product. Thecombined solid material was dissolved in isopropyl alcohol and uponcooling, a fine precipitate formed (N,N-dimethyl-1,3-propanediamineoxalate) which was removed by filtration. The product failed tocrystallize; addition of isopropyl ether gave only an amorphous gel.After trying to obtain a more satisfactory product for 3 weeks, thereaction material was converted to the free base and taken up inisopropyl ether. The ether solution was stirred with 300 ml of waterovernight to remove the diamine. The product crystallized as the freebase from the heterogenous mixture and was filtered to give 11.3 g offine beige crystals. Rework of the filtrate gave an additional 2.3 g ofproduct. A portion (8 g) was recrystallized from benzene/ligroin toyield 5.8 g of very fine beige crystals which were dried at 82° C. undervacuum, m.p. 107°-108° C.

Analysis: Calculated for C₁₆ H₂₂ F₃ N₃ OS: C,53.17; H,6.14; N,11.63

Found: C,53.29; H,6.15; N,11.60

EXAMPLE 7N-(2-Propenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 18.9 g (0.05 mole) of crude3-[3-(trifluoromethyl)phenoxy]azetidine (contains an equal molar amountof diphenylmethane) in 100 ml of isopropyl ether was stirred undernitrogen while 4.16 g (0.05 mole) of 2-propenyl isocyanate was slowlyadded. The reaction mixture which was somewhat turbid, cleared and after1 hr a fine crystalline precipitate began to form. After stirring for 18hrs, the product was removed by filtration, washed with fresh isopropylether and air dried to yield 9.5 g of white crystals, m.p. 75°-76° C.

Analysis: Calculated for C₁₄ H₁₅ F₃ N₂ O₂ : C,56.00; H,5.04; N,9.33

Found: C,55.98; H,5.05; N,9.31

EXAMPLE 8N-Cyclopropyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A mixture of 1.9 g (0.033 mole) of cyclopropylamine and 4.9 g of1,1'-carbonyldiimidazole in 60 ml of tetrahydrofuran was stirred atambient temperature for 1 hr. The clear solution which formed wastreated with a solution of (0.03 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine in 20 ml of tetrahydrofuran.After stirring overnight, the solid precipitate was removed byfiltration to give 4.4 g of gray-white powder. The CI mass spectrumshowed a p+1 at 381 m/e which was consistent with the expected product.Recrystallization from benzene/ligroin gave 2.3 g of a light graypowder, m.p. 152°-153° C.

Analysis: Calculated for C₁₄ H₁₅ F₃ N₂ O: C,56.00 H,5.04; N,9.33

Found: C,55.97; H,5.07; N,9.28

EXAMPLE 9 N-[3-(Diethylamino)propyl]-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide oxalate [1:1,5]

A mixture of 4.3 g (0.033 mole) of 3-diethylaminopropylamine and 4.9 g(0.033 mole) of 1,1'-carbonyldiimidazole in 60 ml of methylene chloridewas stirred at ambient temperature for 1 hr. The resulting solution wastreated with 3-[3-(trifluoromethyl)phenoxy]azetidine (obtained from 9.21g (0.03 mole) of the oxalate salt) in 30 ml of methylene chloride. Afterstirring for 18 hr, the reaction mixture was transferred to a separatoryfunnel and washed with 3×20 ml of water, dried over magnesium sulfateand concentrated in vacuo to a dark oil. The residue (8 g) waschromatogarphed on a 150 g neutral alumina column by eluting withchloroform. Concentration of the initial fraction gave the product as anamber oil which was dissolved in methylisobutyl ketone and treated with2 g of oxalic acid. Dilution with isopropyl ether gave an oil whichsolidified and was recrystallized from acetone/isopropyl ether to give6.25 g (41%) of beige crystals, m.p. 91° -93° C.

Analysis: Calculated for C₁₈ H₂₆ F₃ N₃ O₂.1.5 C₂ H₂ O₄ C,49.61; H,5.75;N,8.26

Found C,49.56; H,5.73; N,8.24

EXAMPLE 10N-(2-Propenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 8.7 g (0.04 mole) of crude3-[4-(trifluoromethyl)phenoxy]azetidine in 75 ml of isopropyl ether wasstirred under a blanket of nitrogen while 4.2 g (0.05 mole) of2-propenyl isocyanate was added dropwise. After stirring for 3 days, nocrystalline product precipitated. The reaction mixture was concentratedto a dark reddish oil. TLC (20% ethyl acetate/methylene chloride onsilica gel) showed at least 6 spots, all well separated. The residue wasdissolved in chloroform, chromatographed on a 350 g silica gel columnand eluted with chloroform until the reddish forerun was removed. Thecolumn was then eluted with an ethyl acetate/chloroform gradient to 4%ethyl acetate. All the fractions were combined and concentrated to give4.8 of orange oil, which crystallized on standing. Recrystallizationfrom acetone/cyclohexane gave 3.3 g (27.5%) of beige crystals, m.p.91°-92.5° C.

Analysis: Calculated for C₁₄ H₁₅ F₃ N₂ O₂ : C,56.00 H,5.04; N,9.33

Found: C,55.98; H,5.17; N,9.36

EXAMPLE 11N-(Cyclopropylmethyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 2.6 g (0.024 mole) of (aminomethyl) cyclopropanehydrochloride in 50 ml of pyridine was stirred under a blanket ofnitrogen while 3.9 g (0.024 mole) of 1,1'-carbonyldiimidazole was added.After stirring for 45 minutes, the TLC (5% methanol/methylene chlorideon silica gel) showed no reaction; therefore, 2 ml of triethylamine wasadded. The reaction mixture after 10 minutes became cloudy and the TLCshowed a new product. The reaction was treated with 6.2 g (0.02 mole) of3-(3-(trifluoromethyl)phenoxy]azetidine oxalate. After stirring for 1hr, a sample was removed, and upon dilution with water, a solidprecipitated. The CI mass spectrum indicated it was product. After 2days, the reaction was diluted with 5 volumes of water and the resultingprecipitate collected by filtration to yield 6.5 g of pale yellowcrystalline product. Recrystallization from ethanol/water produced whiteplate-like crystals which were dried at 82° C. for 3 hr in a dryingpistol under vacuum; weight of the product was 5.8 g (92%), m.p.132°-133° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.22; H,5.44; N,8.86

EXAMPLE 12N,N-Diethyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 5 g (0.0163 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 50 ml oftetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr,2.5 g (0.018 mole) of diethylcarbamoyl chloride was added. Afterstirring an additional 15 hr, the reaction was treated with 10 ml ofwater and saturated with calcium chloride. The tetrahydrofuran wasdecanted from the solid residue and concentrated in vacuo to an oil. Thecrude oil was chromatographed on a Water's Prep-LC using 50% ethylacetate/toluene as the eluent. After concentration of the main fractions3.1 g (60.1%) of pale yellow oil was obtained.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,56.69; H,6.01; N,8.77

EXAMPLE 13N,N-Dimethyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 5 g (0.0163 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 50 ml oftetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr,1.95 g (0.018 mole) of dimethylcarbamoyl chloride was added. Afterstirring an additional 15 hr, the reaction mixture was treated with 20ml of water and 10 g of calcium chloride. The tetrahydrofuran layer wasdecanted and the residue triturated with 20 ml of ethyl acetate, thendecanted. The combined tetrahydrofuran and ethyl acetate solution wasconcentrated in vacuo. The crude residue was chromatographed on a WatersPrep-LC using 50% ethyl acetate/toluene as the eluent. Afterconcentration of the main fractions, 3.6 g (76.6%) of pale yellow oilwas obtained.

Analysis: Calculated for C₁₃ H₁₅ F₃ N₂ O₂ : C,54.17; H,5.25; N,9.72

Found: C,53.73; H,5.20; N,9.60

EXAMPLE 14N-(2-Propynyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide-azetidinecarboxamide

A mixture of 3.9 g (0.024 mole) of 1,1'-carbonyldiimidazole and 1.32 g(0.024 mole) of 2-propynylamine in 50 ml of tetrahydrofuran was stirredat ambient temperature for 1 hr, then treated with 6.2 g of3-[3-(trifluoromethyl) phenoxy]azetidine. The reaction mixture wastreated with 3 ml of triethylamine and stirred for 18 hr. The reactionmixture was diluted with an equal volume of water and filtered to yield8 g of wet product. Recrystallization from isopropyl ether gave 3.8 g ofgray solid, a mixture of product and the symmetrical urea of starting2-propynylamine. A second recrystallization from ethanol-water yielded2.6 g (43.6%) of pure product, m.p. 105°-106° C.

Analysis: Calculated for C₁₄ H₁₃ F₃ N₂ O₂ : C,56.38; H,4.39; N,9.39

Found: C,56.32; H,4.34; N,9.44

EXAMPLE 15N-Cyclohexyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred mixture of 5 g (0.0163 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate and 2.04 g (0.018 mole)of cyclohexyl isocyanate in 50 ml of tetrahydrofuran was treated with 2ml of triethylamine then stirred for 18 hr. Dilution of the mixture withwater gave a solid precipitate which was collected by filtration toyield 12 g of crude product. Recrystallization from acetone/water gave 5g of fine white crystals, m.p. 148°-150° C. TLC (ethyl acetate on silicagel) showed a trace of symmetrical cyclohexyl urea as well as theproduct. A second recrystallization from isopropanol yielded 1.65 g(29.6%) of white powder; dried under 0.5 mm/Hg vacuum, m.p. 153°-154° C.

Analysis: Calculated for C₁₇ H₂₁ F₃ N₂ O₂ : C,59.64; H,6.18; N,8.18

Found: C,59.52; H,6.20; N,8.17

EXAMPLE 16N-Cyclopropyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 4.4 g (0.027 mole) of 1,1'-carbonyldiimidazole in 50ml of methylene chloride under nitrogen was treated with 1.54 g (0.027mole) of cyclopropylamine. After a short (2 min) induction period, theclear solution became suddenly exothermic, bringing the reaction to agentle reflux. After 1 hr when the reaction mixture had cooled toambient temperature, 9.6 g (0.025 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine, 56.66% purity (containsdiphenylmethane) was added all at once and stirring continued for 18 hr.The reaction mixture was concentrated on a rotary evaporator to give apartially crystalline residue. The residue was partitioned between 30/60petroleum ether and water and the resulting waxy solid removed byfiltration. Recrystallization from isopropyl ether yielded 5.7 g (75.9%)of silver plate-like crystals, m.p. 145°-147° C. After drying at 80° C.under 0.5 mm/Hg vacuum, the weight was not diminished, m.p. 152°-153° C.

Analysis: Calculated for C₁₄ H₁₅ F₃ N₂ O₂ : C,56.00; H,5.04; N,9.33

Found: C,55.77; H,4.98 N,9.44

EXAMPLE 17N-(Cyclopropylmethyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred mixture of 4.4 g (0.027 mole) of 1,1'-carbonyldiimidazole and2.9 g (0.027 mole) of (aminoethyl) cyclopropane hydrochloride in 50 mlof methylene chloride was treated with the dropwise addition of 2.73 g(0.027 mole) of triethylamine. The reaction was exothermic. The mixturewas cooled while stirring for 1 hr, then 9.6 g (0.025 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine, 56.66% purity, (containsdiphenylmethane) was added all at once and stirring continued for 18 hr.The reaction mixture was concentrated on a rotary evaporator to give anamber residue. Trituration of this residue with 30/60 petroleum ethergave only an insoluble oil. The trituration step was repeated with 2×20ml of 30/60 petroleum ether and the residue treated with water to yielda white solid. The solid was recrystallized from isopropyl ether toyield 4.8 g (61.8%) of white platelike crystals; after during at 80° C.under 0.5 mm Hg vacuum, m.p. 132°-133° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.26; H,5.46; N,8.93

EXAMPLE 18 N-[3-(Diethylamino)propyl]-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarbothioamide

A stirred solution of 1.92 g (0.005 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine, 56.66% (containsdiphenylmethane) in 20 ml of isopropyl ether was treated with 0.88 g(0.005 mole) of 3-(diethylamino)propyl isothiocyanate and stirred for3.5 hr. The reaction mixture was treated with 0.5 g of oxalic aciddissolved in 2 ml of methanol. After stirring for 18 hr, the solid wascollected by filtration, yielding 1.9 g of fine tan powder, m.p.147°-150° C. The solid was dissolved in water and treated with dilutesodium hydroxide. An oil separated which solidified and was collected byfiltration. Recrystallization from cyclohexane yielded 1.1 g (56.5%) offine tan crystals, m.p. 109°-110° C.

Analysis: Calculated for C₁₈ H₂₆ F₃ N₃ OS: C,55.51; H,6.73; N,10.79

Found: C,55.68; H,6.67 N,10.73

EXAMPLE 19 N-[3-(Diethylamino)propyl]-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide oxalate [1:2]

A stirred solution of 4.4 g (0.027 mole) of 1,1'-carbonyldiimidazole in50 ml of methylene chloride under nitrogen was treated with the dropwiseaddition of 3.52 g (0.027 mole) of 3-(diethylamino)propylamine. Thereaction mixture was stirred for 1 hr as the somewhat exothermicreaction cooled to ambient temperature then treated with 9.6 g (0.025mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine, 56.66% (containsdiphenylmethane) all at once. After stirring for 18 hr, the reactionmixture was concentrated on a rotary evaporator and the residuedissolved in toluene. The toluene solution was washed with 3×20 ml ofwater, then treated with 2.5 g of oxalic acid in 10 ml of isopropanolThe resulting solid was collected by filtration and triturated withboiling acetone. After filtration, 1.8 g of unidentified fine whiteprecipitate formed which was separated by filtration. The acetonesolution was concentrated to a solid which was recrystallized fromisopropyl alcohol/isopropyl ether to yield 9.2 g of crude product (4spots on TLC; 10% methanol/methylene chloride on silica gel).Recrystallization from methyl ethyl ketone yielded 6.8 g (49.1%) of finewhite powder, m.p. 129°-130° C.

Analysis: Calculated for C₁₈ H₂₆ F₃ N₃ O₂.2C₂ H₂ O₄ : C,47.74; H,5.46;N,7.59

Found C,47.82; H,5.68; N,7.76

EXAMPLE 20N-(2-Propynyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 4.4 g (0.027 mole) 1,1'-carbonyldiimidazole in 50 ml oftetrahydrofuran was stirred under nitrogen while 1.49 g (0.027 mole) of2-propynylamine was added with a syringe and needle through a septuminstalled in one neck of the reaction flask. After stirring for 2 hr,9.6 g (0.025 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine (56.66%purity; contains diphenylmethane) was added all at once and stirringcontinued for an additional 18 hr. The reaction mixture was diluted withice-water and extracted with 30/60 petroleum ether to remove thediphenylmethane. The oily aqueous portion was extracted with 4×50 ml ofmethylene chloride. These extracts were combined, dried over sodiumsulfate and concentrated to an amber oil on a rotary evaporator. The oilsolidified when triturated with a small amount of isopropyl ether (50ml). Filtration yielded 6.1 g of rose-tinted solid product. TLC (10%methanol/methylene chloride on silica gel) showed a mixture of 3products and some starting material. Recrystallization fromethanol/water gave the product in several small fractions. These werecombined and recrystallized from isopropyl ether to yield 4.1 g of palebeige powder, m.p. 135°-137° C. TLC still showed some symmetrical2-propynyl urea. The solid was recrystallized again from ethanol/waterto yield 3.5 g (46.9%) of pale yellow crystalline product, m.p.140°-141° C.

Analysis: Calculated for C₁₄ H₁₃ F₃ N₂ O₂ : C,56.38; H,4.39; N,9.39

Found: C,56.34; H,4.36; N,9.32

EXAMPLE 21N-(2-Methyl-2-propenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in75 ml of methylene chloride under nitrogen was treated with 1.6 g (0.022mole) of 2-methyl-2-propenylamine (added via a syringe and needlethrough a septum placed in one neck of the reaction flask). Afterstirring for 1 hr, 6.2 g (0.02 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at oncefollowed in 30 min with 5 ml of triethylamine and stirring was continuedfor 3 hr. The reaction mixture was washed with water (2×25 ml), driedover magnesium sulfate and concentrated in vacuo. The oily residuesolidified on standing and was recrystallized from isopropyl ether toyield 3.7 g (58.9%) of fine white crystals, m.p. 101°-102° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.45; H,5.51; N,9.23

EXAMPLE 22N-(2-Methyl-2-propenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 75 ml ofmethylene chloride was stirred under nitrogen while 1.6 g (0.022 mole)of methallylamine was added with a syringe and needle through a septuminstalled in one neck of the reaction flask. The reaction was slightlyexothermic. The reaction mixture was stirred for 1 hr, then treated with6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalatefollowed in 0.5 hr with 5 ml of triethylamine and stirring continued for16 hr. The reaction mixture was washed with 2×30 ml of water, dried overmagnesium sulfate, and concentrated on a rotary evaporator to yield 6.7g of oily residue which solidified. The residue was recrystallized fromisopropyl ether to yield 5.4 g (85.9%) of fine white crystals, m.p.90°-91° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.20; H,5.50; N,8.95

EXAMPLE 23N-(3-Methyl-2-butenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide.

A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 100 mlof methylene chloride was cooled in a tap water bath and while stirringunder nitrogen, 1.87 g (0.022 mole) of 3-methyl-2-butenylamine was addeddropwise. After stirring for 1 hr, 6.2 g (0.02 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at oncefollowed in 0.5 hr with 5 ml of triethylamine and stirring continued foran additional 16 hr. The reaction mixture was washed with 2×50 ml ofwater, dried over magnesium sulfate and concentrated on a rotaryevaporator to yield a semi-solid residue. Trituration with isopropylether and filtration yielded 7 g of crude product which wasrecrystallized from ethanol-water to give 5.5 g (83.8%) of whitecrystals, m.p. 156.5°-158° C.

Analysis: Calculated for C₁₆ H₁₉ F₃ N₂ O₂ : C,58.53; H,5.83; N,8.53

Found: C,58.81; H,5.89; N,8.58

EXAMPLE 24N-(3-Methyl-2-butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 3.6 g (0.022 mold) of 1,1'-carbonyldiimidazole in 100 mlof tetrahydrofuran was cooled with a tap water bath and stirred undernitrogen while 1.6 g (0.022 mole) of 3-methyl-2-butenylamine was addedwith a syringe and needle. The reaction mixture was stirred for 1 hr,then treated with 6.2 g (0.02 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate followed in 0.5 hr with5 ml of triethylamine and stirring continued for 72 hr. The reactionmixture was diluted with 500 ml of ice water and extracted with 6×50 mlof methylene chloride. The combined extracts were washed with water,dried over magnesium sulfate and concentrated to a solid residue on arotary evaporator. Recrystallization from ethanol-water yielded 6 g ofwhite crystals, m.p. 143°-144° C.

Analysis: Calculated for C₁₆ H₁₉ F₃ N₂ O₂ : C,58.53; H,5.83; N,8.53

Found: C,58.46; H,5.86; N,8.69

EXAMPLE 25(E)-N-(2-Butenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A mixture of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole and 1.6 g(0.022 mole) of trans-crotylamine was stirred for 1 hr, then treatedwith 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidineoxalate and followed in 0.5 hr with 5 ml of triethylamine with stirringcontinued for 16 hr. The partially crystalline mixture was washed with2×50 ml of water, dried over magnesium sulfate and concentrated on arotary evaporator to a solid residue, 14.2 g. Recrystallization frommethanol-water yielded 5.35 g (85.1%) of fine white crystals, m.p.157°-158° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.47; H,5.49; N,9.00

EXAMPLE 26(E)-N-(2-Butenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 60 ml ofmethylene chloride was cooled in an ice bath while stirring undernitrogen while 1.6 g (0.022 mole) of trans-crotylamine was addeddropwise. After warming to ambient temperature, 6.2 g (0.02 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at oncefollowed in 0.25 hr by 5 ml of triethylamine with stirring continued for72 hr. The reaction solution was washed with 2×50 ml of water, driedover magnesium sulfate and concentrated on a rotary evaporator to asolid residue, 7 g. Recrystallization from methanol-water gave 5.5 g ofslightly yellow product. A second recrystallization with charcoaltreatment from isopropyl ether yielded 3.75 g (59.7%) of fine whitecrystals, m.p. 127°-128° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.35; H,5.47; N,8.94

EXAMPLE 27N-Phenyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 6.2 g (0.02 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml oftetrahydrofuran was treated with 5 ml of triethylamine followed by 2.62g (0.022 mole) of phenyl isocyanate and stirring continued for 16 hr.The reaction mixture was diluted with water until an oil separated whichquickly solidified. The aqueous tetrahydrofuran was decanted and thesolid residue recrystallized from ethanol-water to yield 5.3 g (80.1%)of white crystals, m.p. 137°-138° C.

Analysis: Calculated for C₁₇ H₁₅ F₃ N₂ O₂ : C,60.71; H,4.50N,8.33

Found: C,60.81; H,4.47; N,8.35

EXAMPLE 28N-Phenyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 6.2 g (0.02 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine oxalate and 2.62 g (0.022 mole)of phenyl isocyanate in 60 ml of tetrahydrofuran was treated with 5 mlof triethylamine and stirring continued for 16 hr. The reaction mixturewas diluted with water until an oil separated. The tetrahydrofuran-waterportion was decanted and the residue solidified on standing.Recrystallization from ethanol-water yielded 3.5 g (53.4%) of fine whitecrystals, m.p. 174.5°-176° C.

Analysis: Calculated for C₁₇ H₁₅ F₃ N₂ O₂ : C,60.71; H,4.50N,8.33

Found: C,60.91; H,4.53; N,8.35

EXAMPLE 29trans-N,2-Dimethyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred solution of 6 g (0.015 mole) of crudetrans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml oftetrahydrofuran was treated with 0.94 g (0.0165 mole) of methylisocyanate added dropwise and stirred for 16 hr under a blanket ofnitrogen. Dilution of the reaction mixture with water produced an oilwhich solidified. After decanting the aqueous tetrahydrofuran phase, thesolid residue was recrystallized from ethanol-water to yield 3.95 g(91.4%) of fine white crystals, m.p. 104.5°-106° C.

Analysis: Calculated for C₁₃ H₁₅ F₃ N₂ O₂ : C,54.17; H,5.25; N,9.72

Found: C,54.50; H,5.29; N,9.71

EXAMPLE 30trans-2-Methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A mixture of 6 g (0.015 mole) of crudetrans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (purity 56.6%contains diphenylmethane) and 2.4 g (0.0225 mole) of nitrourea in 40 mlof acetone was treated with 4 ml of water, then heated until a clearhomogenous solution was obtained. The reaction mixture was stirredovernight as it cooled to ambient temperature and diluted with wateruntil an oil separated. The oil solidified and was recrystallized fromethanol/water, yielding 4.3 g of white plate-like crystals; m.p.117°-118° C. The product was recrystallized from benzene, yielding 3.35g (96.8%) of crystals, m.p. 118°-119° C.

Analysis: Calculated for C₁₂ H₁₃ F₃ N₂ O₂ : C,52.56; H,4.78; N,10.22

Found: C,52.54; H,4.74; N,10.17

EXAMPLE 31 trans-2-Methyl-N-(2-propenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 6 g (0.015 mole) of crudetrans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (56.6%) in 50 mlof tetrahydrofuran was treated with 1.54 g (0.0165 mole) of 2-propenylisocyanate all at once and stirred under a blanket of nitrogen for 16hr. The reaction mixture was diluted with water until an oil separated.The oil failed to crystallize and after 7 weeks it was triturated withisopropyl ether (3×25 ml). The combined triturates gave 400 mg of whitegranular crystals (8.5%), m.p. 55°-57° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.36; H, 5.50; N,8.97

EXAMPLE 32 3-(3-Chlorophenoxy)-N-methyl-1-azetidinecarboxamide

A solution of 1-chlorocarbonyl-3-(3-chlorophenoxy) azetidine (0.01275mole) in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mole) of40% aqueous methylamine and stirred for 16 hr. The reaction mixture wasdiluted with water until an oil began to separate, then extracted with3×50 ml of benzene. The combined extracts were dried over magnesiumsulfate and concentrated to a solid which was recrystallized frombenzene/ligoin to yield 1.2 g (40.0%) of fine white crystals, m.p.140°-141° C.

Analysis: Calculated for C₁₁ H₁₃ ClN₂ O₂ : C,54.89; H,5.44; N,11.64

Found: C,55.05; H,5.58; N,11.52

EXAMPLE 33 3-(3-Chlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A solution of 5.4 g (0.017 mole) of1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine in 20 ml oftetrahydrofuran was treated with 2.3 g (0.04 mole) of 2-propenylamineand stirred for 2 hr. The reaction solution was concentrated in vacuo toa rose beige solid. Trituration of the solid with water gave, afterfiltering, 4.4 g of crude product. After drying, the solid wasrecrystallized with charcoal treatment from 2% acetone/isopropyl etherto yield 1.7 g (37.5%) of pale beige crystals, m.p. 87°-89° C.

Analysis: Calculated for C₁₃ H₁₅ ClN₂ O₂ : C,58.54; H,5.67; N,10.50

Found: C,58.48; H,5.72; N,10.49

EXAMPLE 34 N-Methyl-3-(2-pyridinyloxy)-1-azetidinecarboxamide

A 2M benzene solution of phosgene (40 ml, 0.08 mole) was added to asuspension of 10 g of finely ground potassium carbonate in 40 ml ofmethylene chloride. The mixture was stirred for 15 min. at roomtemperature and 10 g (0.056 mole) of1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml of methylenechloride was added with mild cooling. The mixture was stirred at roomtemperature for 1 hr and concentrated on a rotary evaporator (25° C./30mm). The residue was treated with 100 ml of tetrahydrofuran and cooledwith an ice bath. To the cooled, stirred mixture was added 20 ml of 40%aqueous methylamine. The mixture was stirred for 20 min and partitionedbetween methylene chloride and water. The methylene chloride was driedover sodium sulfate and concentrated. The residue was crystallized frombenzene-ethanol and recrystallized from ethyl acetate-isopropyl alcohol.Yield of title compound was 2.3 g (14%), m.p. 165°-168° C.

Analysis: Calculated for C₁₀ H₁₃ N₃ O₂ : C,57.96; H,6.32; N,20.28

Found: C,57.93; H,6.34; N,20.12

EXAMPLE 35 N-(2-Propenyl)-3-(2-pyridinyloxy)-1-azetidinecarboxamide

To a stirred suspension of 10 g (0.072 mole) of finely ground potassiumcarbonate in 90 ml of methylene chloride was added 32 ml (0.062 mole) of2M phosgene in benzene. The mixture was stirred for 15 min and 8 g(0.031 mole) of 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml ofmethylene chloride was added. The mixture was stirred at 25° C. for 2 hrand concentrated on a rotary evaporator at 25° C./30 mm and the residuewas treated with 100 ml of tetrahydrofuran. The stirred mixture wascooled with an ice bath and treated dropwise with 4 g (0.07 mole) ofallyl amine. After stirring 30 min at 25° C., the material waspartitioned between water and methylene chloride. The methylene chloridewas dried and concentrated. The residue was chromatographed on a Waters®PREP-500 HPLC using a silica column and eluting with 50%ethylacetate-hexane. The product was crystallized twice from isopropylether. Yield of title compound was 1.5 g (21%), m.p. 72°-76° C.

Analysis: Calculated for C₁₂ H₁₅ N₃ O₂ : C,61.79; H,6.48; N,18.01

Found: C,61.53; H,6.50; N,17.96

EXAMPLE 36 3-(2-Pyridinyloxy)-1-azetidinecarboxamide

A 2M benzene solution of phosgene (32 ml, 0.062 mole) was added to astirred suspension of 10 g of finely ground potassium carbonate in 80 mlof methylene chloride. The mixture was stirred for 15 min and 8 g (0.031mole) of 1-(1-phenylethyl)-3-(2-pyridyloxy)azetidine in 50 ml ofmethylene chloride added. The mixture was stirred for 35 min andconcentrated on a rotary evaporator (25° C./30 mm). The residue wastreated with 100 ml of tetrahydrofuran, cooled with an ice bath and 20ml of concentrated ammonium hydroxide added slowly while stirringvigorously. The mixture was stirred 1 hr at room temperature andpartitioned between methylene chloride and water. The water layer wasextracted 2 times with methylene chloride and the combined organiclayers were concentrated. The residue was crystallized from benzene andrecrystallized from isopropyl ether. Yield of title compound was 1.4 g,m.p. 133°-137° C.

Analysis: Calculated for C₉ H₁₁ N₃ O₂ : C,55.95; H,5.74; N,21.75

Found: C,55.73; H,5.71; N,21.10

EXAMPLE 371-Propyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazinefumarate [1:1]

A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 4.2 g (0.03 mole) of potassiumcarbonate in 25 ml of tetrahydrofuran was stirred for 10 min, thentreated with 2.9 g (0.01 mole) of 1-propylpiperazine dihydrobromide insmall portions. After 30 min, a few pieces of ice were added. Afterstirring for 17 hr, the reaction was diluted with 200 ml of water thenextracted with methylene chloride (2×50 ml). The combined extracts weredried over magnesium sulfate and concentrated in vacuo, yielding 4.84 gof crude residue. The residue was converted to the fumarate salt in2-propanol, concentrated to a solid in vacuo and recrystallized fromacetone with a trace of ethanol to yield 2.9 g (59.5%) of fine whitecrystals; m.p. 117°-123° C.

Analysis: Calculated for C₁₈ H₂₄ F₃ N₃ O₂.C₄ H₄ O₄ : C,54.21; H,5.79;H,8.62

Found C,54.62; H,6.08; N,8.34

EXAMPLE 381-[3-[4-(Trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]-1H-imidazole

A mixture of 1.7 g (0.01 mole) 1,1'-carbonyldiimidazole in 50 ml oftetrahydrofuran and 3 g (0.015 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine was stirred for 6 hr. Thereaction mixture was diluted with water and extracted with 3×50 ml ofmethylene chloride. The extracts upon concentrating in vacuo gave anamber residue which was dissolved in 20 ml of benzene and washed withdilute hydrochloric acid, then washed with water. The benzene portionwas concentrated to give a semi-solid residue which when triturated withisopropyl ether gave 1.4 g of gray material. Recrystallization fromacetonitrile gave 1.3 g (41.8%) of fine gray crystals, m.p. 139°-140° C.

Analysis: Calculated for C₁₄ H₁₂ F₃ N₃ O₂ : C,54.02; H,3.89; N,13.50

Found: C,54.33; H,3.96; N,13.89

EXAMPLE 39 N-Methyl-3-phenoxy-1-azetidinecarboxamide

The compound was prepared from the methane sulfonate of3-phenoxyazetidine and methylisocyanate as described in Example 1 ofU.S. Pat. No. 4,226,861, m.p. 139°-141° C.

EXAMPLE 40N-Methyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

The compound was prepared from 3-[4-(trifluoromethylphenoxy)azetidineand methylisocyanate as described in Example 3 of U.S. Pat. No.4,226,861, m.p. 154°-157° C.

EXAMPLE 41N-Methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

The compound was prepared from 3-[3-(trifluoromethyl)phenoxy)azetidineand methylisocyanate as described in Example 4 of U.S. Pat. No.4,226,861, m.p. 145°-147° C.

EXAMPLE 42N-Methyl-3-[2-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

The compound was prepared from 3-[2-(trifluoromethyl)phenoxy)azetidineand methylisocyanate as described in Example 5 of U.S. Pat. No.4,226,861, m.p. 134°-136° C.

EXAMPLE 43 N-Methyl-3-[2-(aminocarbonyl)phenoxy]-1-azetidinecarboxamide

The compound was prepared from 2-(3-azetidinyloxy) benzamide andmethylisocyanate as described in Example 2 of U.S. Pat. No. 4,226,861,m.p. 236°-240° C.

EXAMPLE 44 N-Methyl-3-[3-(aminocarbonyl)phenoxy]-1-azetidinecarboxamide

The compound was prepared from 3-(3-azetidinyloxy) benzamide andmethylisocyanate as described in Example 6 of U.S. Pat. No. 4,226,861,m.p. 238°-240° C.

EXAMPLE 45 N-Methyl-3-[4-(aminocarbonyl)phenoxy]-1-azetidinecarboxamide

The compound was prepared from 4-(3-azetidinyloxy) benzamide andmethylisocyanate as described in Example 7 of U.S. Pat. No. 4,226,861,m.p. 208°-210° C.

EXAMPLE 46 3-[3-(Trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A mixture of 30.6 g (0.141 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine and 42 g (0.321 mole) ofnitrourea (80%) in 500 ml of acetone was stirred for 5 days (5 days notrequired, but convenient) at room temperature. The mixture was filteredand the filtrate concentrated in vacuo. The residue was partitionedbetween 150 ml of water and 100 ml of ethyl acetate and the layersseparated. The aqueous layer was washed with 100 ml of ethyl acetate.The ethyl acetate layers were washed with 75 ml of 5% aqueous sodiumhydroxide solution followed by 75 ml of water, dried over sodium sulfateand concentrated in vacuo. The residual oil was crystallized from ethylalcohol-ethyl acetate to give 22 g (60%) substantially the titlecompound. Recrystallization twice from ethyl alcohol gave 9.9 g of whitecrystalline solid, m.p. 151°-152.5° C.

Analysis: Calculated for C₁₁ H₁₁ F₃ N₂ O₂ :C,50.77; H,4.26; N,10.76

Found: C,50.90; H,4.29; N,10.71

EXAMPLE 47 N-Ethyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

To a stirred and chilled (15°-20° C.) solution of 0.024 mole of3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of dry benzene wasadded dropwise 1.99 g (0.028 mole) of ethyl isocyanate. The reactionmixture was stirred at room temperature overnight and was diluted with50 ml of methylene chloride. The solution was washed with 5% sodiumhydroxide (2×50 ml), water (50 ml), saturated sodium chloride (25 ml),dried over sodium hydroxide, and concentrated in vacuo. The residue (9.6g) was twice recrystallized from ethyl acetate-isopropyl ether to give5.4 g of a white solid, m.p. 125°-126° C.

Analysis: Calculated for C₁₃ H₁₅ F₃ N₂ O₂ :C,54.16;H,5.24; N,9.72

Found: C,54.24; H,5.23; N,9.25

EXAMPLE 48N-(1-Methylethyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

To a stirred and chilled (10°-20° C.) solution of 9.0 g (0.042 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry methylenechloride was added dropwise 4.1 g (0.048 mole) of isopropyl isocyanate.The reaction mixture was stirred at room temperature for 2 hr and wasdiluted with 100 ml of methylene chloride. The solution was washed with5% sodium hydroxide (2×40 ml), water (50 ml), saturated sodium chloride(50 ml), dried (sodium sulfate) and concentrated in vacuo. The residuewas crystallized from ethyl acetate, affording 7.6 g (60.6%).Recrystallization from ethyl acetate gave 5.0 g of clear white needles,m.p. 150°-151.5° C.

Analysis: Calculated for C₁₄ H₁₇ F₃ N₂ O₂ : C,55.62; H,5.68; N,9.27

Found: C,55.77; H,5.68; N,9.22

EXAMPLE 49N-Propyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

To a stirred and chilled (10°-15° C.) solution of 0.027 mole of3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry benzene wasadded dropwise 4.0 g (0.047 mole) of n-propyl isocyanate. The reactionmixture was stirred at room temperature for 30 minutes. The benzene waswashed with dilute sodium bicarbonate (50 ml), water (25 ml), saturatedsodium chloride (25 ml), and dried (sodium sulfate). The solution volumewas reduced to 50 ml, and 30 ml of petroleum ether was added, yielding6.5 g (81%) of product. Recrystallization from isopropyl ether-isopropylalcohol gave 6.0 g of small white needles, m.p. 115°-117° C.

Analysis: Calculated for C₁₄ H₁₇ F₃ N₂ O₂ : C,55.63; h,5.67; N,9.27

Found: C,55.65; H,5.68; N,9.25

EXAMPLE 50 N-Butyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 18.9 (0.05 mole) of crude3-[3-(trifluoromethyl)-phenoxy]azetidine (contains an equal molar amountof diphenylmethane) in 100 ml of isopropyl ether was stirred undernitrogen while 4.96 g (0.05 mole) of N-butyl isocyanate was slowlyadded. The clear reaction solution became warm to the touch, and after20 minutes a white crystalline solid began to precipitate. Afterstirring for 16 hr, the solid was removed by filtration, washed withfresh isopropyl ether and air dried to yield 8 g of pale beige crystals,m.p. 108°-109° C.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,56.78; H,6.06; N,8.83

EXAMPLE 51 N-Ethyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 6.5 g (0.03 mole) of crude3-[4-(trifluoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether wasstirred under a blanket of nitrogen while 2.85 g (0.04 mole) of ethylisocyanate was added dropwise. After stirring for 2 hr at ambienttemperature, a solid began to precipitate, and after 4 hr, the solid wascollected by filtration to yield 3.7 g of beige product, m.p. 94°-96° C.Rework of the filtrate gave only a trace of additional product. Theproduct was recrystallized from isopropyl ether/hexane (treated withcharcoal) to yield 2.61 g (30%) of product, m.p. 109°-110° C.

Analysis: Calculated for C₁₃ H₁₅ F₃ N₂ O₂ : C,54.17; H,5.25; N,9.72

Found: C,54.40; H,5.33; N,9.89

EXAMPLE 52 N-Butyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 6.5 g (0.03 mole) of crude3-[4-(trifluoromethyl)phenoxy]azetidine in 50 ml of isopropyl ether wasstirred under a blanket of nitrogen while 4 g (0.04 mole) of n-butylisocyanate was added dropwise. The reaction was slightly exothermic andafter 30 min, a solid separated. The solid was collected by filtrationafter 3 hr to give 3.85 g of crystalline product, m.p. 135°-136° C.After 24 hr, a second bath of crystals was obtained; 1.5 g; m.p.132°-134° C. The two fractions were combined and recrystallized fromcyclohexane to yield 3.6 g of product (38%), m.p. 136°-137° C.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,57.12; H,6.13; N,8.93

EXAMPLE 53N-Propyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 8.7 g (0.04 mole) of crude3-[4-(trifluoromethyl)phenoxy]azetidine in 75 ml of isopropyl ether wasstirred under a blanket of nitrogen while 4.3 g (0.05 mole) of n-propylisocyanate was added dropwise. After stirring for 2 hr, only a trace ofcrystalline precipitate formed in the reaction mixture, and afterstirring for 18 hr, filtration yielded only 1.1 g of product, m.p.112°-114° C. The filtrate was concentrated in vacuo to give a dark amberresidue. After 3 days, only 1.3 g of additional crude product could beobtained from isopropyl ether/hexane. All of the reaction products weredissolved in chloroform and chromatographed on a 200 g silica gelcolumn. Elution with chloroform gave a reddish forerun, which wasdiscarded. The elution was changed to 2% ethyl acetate/chloroform, thento 4% ethyl acetate, and finally to 2% methanol/chloroform. All thefractions were combined and concentrated to yield 4.1 g of white solid.Recrystallization from cyclohexane yielded 2.86 (23.6%) of fine whitecrystalline product, m.p. 119°-120° C.

Analysis: Calculated for C₁₄ H₁₇ F₃ N₂ O₂ : C,55.63; H,5.67; N,9.27

Found: C,55.50; H,5.77; N,9.19

EXAMPLE 54 3-[4-(Trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 9.6 g (0.025 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine 56.66% (containsdiphenylmethane) in 50 ml of acetone was treated with 4.22 g (0.045mole) of nitrourea and 5 ml of water. The mixture was heated on a hotplate until a clear solution was obtained then allowed to cool toambient temperature during the next 4 hr. The reaction mixture wasdiluted with 200 ml of ice water and an oil separated (diphenylmethane)which was dissolved in 30/60 petroleum ether and separated. Uponstanding, a fine white precipitate formed in the aqueous solution.Filtration yielded 3.6 g of fine white crystals, m.p. 176°-178° C. Afterdrying under 0.5 mm Hg vacuum at 80° C., the product weight was reducedto 3.1 g (47.7%), m.p. 178°-179° C.

Analysis: Calculated for C₁₁ H₁₁ F₃ N₂ O₂ : C,50.74; H,4.26; N,10.77

Found: C,50.72; H,4.24; N,10.72

EXAMPLE 55N-(1-Methylethyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 6.2 g (0.02 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml oftetrahydrofuran was treated with 1.8 g (0.022 mole) of 1-methylethylisocyanate and after 0.5 hr, 5 ml of triethylamine was added. A clearyellow solution was obtained and was stirred for 18 hr, then treatedwith 10 ml of water, yielding 5.3 g (87.7%) of pale yellow crystals,m.p. 151°-152° C.

Analysis: Calculated for C₁₄ H₁₇ F₃ N₂ O₂ : C,55.63; H,5.67; N,9.27

Found: C,55.80; H,5.71; N,9.24

EXAMPLE 56N-(1,1-Dimethylethyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 6.2 g (0.02 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml oftetrahydrofuran was treated with 2 g (0.022 mole) of 1,1-dimethylethylisocyanate and after 0.5 hr 5 ml of triethylamine was added. Thereaction slurry quickly turned to a pale yellow solution which wasstirred for 18 hr, then treated with 10 ml of water. After 20 min, thetetrahydrofuran portion was separated, dried over magnesium sulfate andconcentrated on a rotary evaporator. The solid residue wasrecrystallized from isopropyl ether to yield 5 g (79.0%) of fine whitecrystals, m.p. 145°-146° C.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,56.97; H,6.15; N,8.86

EXAMPLE 57N-(2-Methylpropyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in100 ml of methylene chloride under nitrogen was treated with 1.6 g(0.022 mole) of 2-methylpropylamine (added via a syringe and needlethrough a septum placed in one neck of the reaction flask). Afterstirring for 1 hr, 6.2 g (0.02 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at oncefollowed in 30 min with 5 ml of triethylamine and stirring continued for18 hr. The reaction mixture was washed with water (2×25 ml), dried overmagnesium sulfate and concentrated in vacuo, yielding 13 g of crudesolid residue. Recrystallization from ethanol/water yielded 5.9 g ofproduct having a pink cast. A second recrystallization from cyclohexaneyielded 4.8 g of fine white crystals, m.p. 124°-125° C. Rework of thefiltrates yielded 1.2 g additional beige crystals.

Total yield of product was 75.6% of theory.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,57.01; H,6.11; N,8.88

EXAMPLE 58N-(1,1-Dimethylethyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred slurry of 6.2 g (0.02 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml oftetrahydrofuran was treated with 2 g (0.02 mole) of 1,1-dimethylethylisocyanate followed in 30 min with 5 ml of triethylamine. The clearsolution which developed was stirred for 18 hr. The reaction mixture wastreated with 10 ml of water and after 20 min, the tetrahydrofuranportion was separated, dried over magnesium sulfate, and concentrated ona rotary evaporator. The solid residue was recrystallized fromethanol/water, yielding 5.8 g (91.7%) of fine white crystals, m.p.105°-107° C.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,56.95; H,6.14; N,8.92

EXAMPLE 59 N-(2-Methylpropyl)-3-[4-(trifluoromethyl)phenoxy]-1azetidinecarboxamide

A stirred solution of 3.6 g (0.022 mole) of 1,1-carbonyldiimidazole in100 ml of methylene chloride under nitrogen was treated with 1.6 g(0.022 mole) of 2-methylpropylamine (added via a syringe and needlethrough a septum placed in one neck of the reaction flask). Afterstirring for 1 hr, 6.2 g (0.02 mole) of3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at oncefollowed in 30 min with 5 ml of triethylamine and stirring was continuedfor 18 hr. The reaction mixture was washed with water (2×25 ml), driedover magnesium sulfate, and concentrated in vacuo. The solid residue wasrecrystallized from ethanol/water, yielding 5.4 g (85.4%) of pale yellowcrystals.

Analysis: Calculated for C₁₅ H₁₉ F₃ N₂ O₂ : C,56.96; H,6.05; N,8.86

Found: C,57.02; H,6.08; N,8.82

EXAMPLE 60 3-(3-Chlorophenoxy)-1-azetidinecarboxamide

A solution of 5.4 g (0.017 mole) of1-chlorocarbonyl-3-(3-chlorophenoxy)azetidine in 20 ml oftetrahydrofuran was treated with 3 ml of ammonium hydroxide and stirredfor 1 hr. The reaction mixture was concentrated in vacuo to a wet solid,4 g, which was recrystallized after drying, from benzene to yield 1.5 gof white crystalline powder, m.p. 163°-164.5° C. Yield calculated fromthe 1-(2-phenylethyl)azetidine compound was 38.9%.

Analysis: Calculated for C₁₀ H₁₁ ClN₂ O₂ : C,52.99; H,4.89; N,12.36

Found: C,52.99; H,4.91 N,12.32

EXAMPLE 61 3-(3-Fluorophenoxy)-N-methyl-1-azetidinecarboxamide

A stirred mixture of 5.4 g (0.02 mole) of 3-(3-fluorophenoxy)-azetidineoxalate and 1.7 g (0.022 mole) of methyl isocyanate in 20 ml oftetrahydrofuran was treated with 5 ml of triethylamine then stirring wascontinued for 3 hr. The reaction was diluted with water and the finecrystalline precipitate obtained was collected by filtration and driedat 60° C. under vacuum to yield 3 g (66.9%) of product, m.p. 155°-156°C.

Analysis: Calculated for C₁₁ H₁₃ FN₂ O₂ : C,58.92; H,5.84; N,12.49

Found: C,58.93; H,5.91; N,12.26

EXAMPLE 62 3-(3-Fluorophenoxy)-N-methyl-1-azetidinecarboxamide

A stirred slurry of 0.38 g (0.02 mole) of 60% sodium hydride as amineral oil suspension in 10 ml of dry dimethylformamide was treatedunder nitrogen with the dropwise addition of 1.12 g (0.01 mole) of3-fluorophenol in 20 ml of dimethylformamide. After 1 hr, the mixturewas heated at 90° C. for 20 min then 2.1 g (0.01 mole) ofN-methyl-3-[(methanesulfonyl)oxy]-1-azetidinecarboxamide was added as asolid. The reaction mixture was then stirred at 90° C. for 8 hr. Thereaction mixture was cooled by adding ice water then further diluted to200 ml with water and extracted with 3×50 ml of methylene chloride. Lessthan 1 g of oil was obtained upon concentrations of the extracts.Extraction with 4×50 ml of benzene gave only a trace of product. Themass spectrum (CI) showed the expected p+1 at 225 m/e. The productsolidified on standing and was recrystallized from methanol/water toyield 650 mg (29.0%) of flake-like silver crystals, m.p. 156°-158° C.

Analysis: Calculated for C₁₁ H₁₃ FN₂ O₂ : C,58.92; H,5.84; N,12.49

Found C,58.93; H,5.91; N,12.42

EXAMPLE 63 3-(3-Fluorophenoxy)-1-azetidinecarboxamide

A stirred slurry of 3 g (0.012 mole) of 3-(3-fluorophenoxy)azetidineoxalate [1:1] in 20 ml of acetone was treated with 3 ml of triethylamineand stirred for 1 hr. The resulting solution was treated with 2.5 g(0.024 mole) of nitrourea and 2 ml of water then stirred for 16 hr. Thereaction mixture was diluted with water and the product crystallized.Recrystallization from methanol-water yielded 1.1 g (43.6%) of a whitecrystalline solid, m.p. 169°-170° C.

Analysis: Calculated for C₁₀ H₁₁ FN₂ O₂ : C,57.14; H,5.28; N,13.33

Found: C,57.49; H,5.31; N,13.41

EXAMPLE 641-[3-[3-(Trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]homopiperidine

A solution of 5.6 g (0.02 mole) of1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml oftetrahydrofuran was treated with 3 g (0.022 mole) of potassium carbonateand while stirring, 2.3 g (0.022 mole) of hexamethyleneimine was added.This mixture was treated with 10 g of ice and stirred for 2 hr. Thetetrahydrofuran was decanted and concentrated to an oil residue, 8.1 g.The residue was dissolved in benzene and washed first with diluted acidthen with water, dried over magnesium sulfate and concentrated on arotary evaporator to a pale yellow oil. The oil crystallized when cooledto -70° C. and was recrystallized from hexane to give fine whitecrystals, 5 g (75%); m.p. 64.5°-66° C.

Analysis: Calculated for C₁₇ H₂₁ F₃ N₂ O₂ : C,59.64; H,6.18; N,8.18

Found: C,59.61; H,6.05; N,8.19

EXAMPLE 651-[3-[3-(Trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperidine

A solution of 5.6 g (0.02 mole) of1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml oftetrahydrofuran was treated with 3 g (0.022 mole) of potassium carbonateand while stirring, 1.9 g (0.022 mole) of piperidine was added dropwise.The mixture was then treated with 10 g of ice and stirred for 2 hr. Thetetrahydrofuran was decanted then concentrated on a rotary evaporator toyield an amber oil, 6.9 g. The oil was dissolved in benzene, washed withdilute acid then water, dried over magnesium sulfate and concentrated invacuo. This oil crystallized when cooled to -70° C. and wasrecrystallized from hexane with charcoal treatment at 0° C. yieldingpale tan crystals, 4.5 g (68.5%), m.p. 50°-52° C.

Analysis: Calculated for C₁₆ H₁₉ F₃ N₂ O₂ : C,58.53; H,5.83; N,8.53

Found: C,58.44; H,5.70; N,8.51

EXAMPLE 661-(1-Azetidinylcarbonyl)-3-[3-(trifluoromethyl)phenoxy]azetidine

A mixture of 5.6 g (0.02 mole) of1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.027mole) of potassium carbonate in 50 ml of tetrahydrofuran was treatedwith 1.26 g (0.022 mole) of azetidine added dropwise to the stirredmixture. After stirring for 15 min, the reaction was treated with 10 gof ice and stirred for an additional 72 hr. The tetrahydrofuran wasdecanted from the salt-paste and concentrated on a rotary evaporator toyield an oil, 6.3 g. This oil crystallized when cooled to -70° C. andwas recrystallized from hexane yielding 5.1 g (85%) of fine whitecrystals, m.p. 65°-68° C.

Analysis: Calculated for C₁₄ H₁₅ F₃ N₂ O₂ : C,56.00; H,5.04; N,9.33

Found: C,55.98; H,5.00; N,9.37

EXAMPLE 671-[3-[3-(Trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]pyrrolidine

A mixture of 5.6 g (0.02 mole) of1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.02mole) of potassium carbonate in 50 ml of tetrahydrofuran was stirredwhile 1.57 g (0.022 mole) of pyrrolidine was added all at once. Afterstirring for 15 min, 10 g of ice was added and stirring continued for anadditional 72 hr. The tetrahydrofuran was decanted from the salt pasteand concentrated on a rotary evaporator to yield a yellow oil, 7.2 g.The oil solidified when cooled to -70° C. and was recrystallized fromhexane to yield 3.95 g (64.5%) of silver-white, platelike crystals, m.p.107°-108° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.65; H,5.45; N,8.99

EXAMPLE 68 N-Methyl-N-(2-propynyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A mixture of 5.6 g (0.02 mole) of1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.022mole) of potassium carbonate in 50 ml of tetrahydrofuran was treatedwhile stirring with 1.52 g of N-methylpropargylamine. After stirring for15 min, 10 g of ice was added and stirring continued for an additional72 hr. The tetrahydrofuran was decanted from the salt paste andconcentrated on a rotary evaporator to yield an amber oil, 5.9 g. Thisoil solidified when cooled to -70° C. and was recrystallized from hexaneto yield 4.6 g (74.2%) of fine white crystals, m.p. 71°-73° C.

Analysis: Calculated for C₁₅ H₁₅ F₃ N₂ O₂ : C,57.69; H,4.84; N,8.97

Found: C,58.01; H,4.76; N,9.00

EXAMPLE 691-Methyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazineoxalate [1:1.5]

A solution of 5.6 g (0.02 mole) of1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml oftetrahydrofuran was cooled to 5° C. and while stirring, treated with 5 g(0.05 mole) of 1-methylpiperazine added all at once. The reaction wasallowed to warm to ambient temperature while stirring approximately 18hr. The reaction mixture was diluted 10 fold with water and extractedwith 3×50 ml of methylene chloride. The extracts were combined, driedover magnesium sulfate, filtered and concentrated in vacuo to a yellowoil, 6.8 g. The oil was dissolved in acetone and treated with 2 g ofoxalic acid. A clear solution was obtained when heated to boiling andupon cooling, the product precipitated. Filtration yielded a fine whitecrystalline product, 8.1 g (84.7%), m.p. 144°-145° C.

Analysis: Calculated for C₁₆ H₂₀ F₃ N₃ O₂.1.5C₂ H₂ O₄ : C, 47.70;H,4.85; N,8.78

Found C, 47.71; H,4.85; N,8.74

EXAMPLE 701-Methyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazinefumarate [1:1]

The same procedure as used to prepare1-methyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazineoxalate [1:1.5] was followed except the free base was converted to thefumarate salt (instead of the oxalate salt) by dissolving the residueobtained from work-up in 5 ml of isopropanol and treating this solutionwith 1.2 g of fumaric acid dissolved in 25 ml of boiling isopropanol Thecooled mixture yielded 1.3 g of white product. The filtrate wasconcentrated in vacuo and the resulting solid was combined with the 1.3g of product previously obtained. Recrystallization fromisopropanol/isopropyl ether gave 3.3 (91.8%) of fine white crystals,m.p. 132°-133° C.

Analysis: Calculated for C₁₆ H₂₀ F₃ N₃ O₂.C₄ H₄ O₄ : C,52.29; H,5.27;N,9.15

Found: C,52.42; H,5.21; N,9.13

EXAMPLE 71N-(4-Methylphenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

To a stirred mixture of 1.88 g (0.0067 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1 g(0.007 mole) of potassium carbonate was added 20 ml of tetrahydrofuranand 0.75 g (0.007 mole) of 4-toluidine. After stirring for 0.5 hr, icewas added and stirring continued for 18 hr. The reaction mixture wasdiluted with water and then decanted from an oil residue whichseparated. Upon standing, this residue solidified and was recrystallizedfrom acetone to yield 1.1 g (47%) of large, white crystals, m.p.191°-192° C.

Analysis: Calculated for C₁₃ H₁₇ F₃ N₂ O₂ : C, 61.71; H, 4.85; N, 8.00

Found: C,61.64; H,4.78; N,7.99

EXAMPLE 72N-(4-Chlorophenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A mixture of 5.4 g (0.02 mole) of3-[3-(trifluoromethyl)phenoxy]azetidine oxalate [1:1] and 3.38 g (0.022mole) of 4-chlorophenyl isocyanate was stirred in 20 ml oftetrahydrofuran for 15 min then treated with 5 ml of triethylamine. Thereaction mixture was exothermic and was stirred for 18 hr as it cooledto ambient temperature. The reaction mixture was diluted with 100 ml ofwater and the residue which separated solidified. Filtration yielded 8.9g of crude wet solid. Recrystallization from methyl isobutyl ketone and30/60 petroleum ether yielded 3.65 g (49.7%) of fine white crystals,m.p. 138°-140° C.

Analysis: Calculated for C₁₇ H₁₄ ClFN₂ O₂ : C,55.07; H,3.81; N,7.56

Found: C,55.16; H,3.79; N,7.70

EXAMPLE 73 3-(4-Fluorophenoxy)-N-methyl-1-azetidinecarboxamide

A solution of 4.6 g (0.02 mole) of3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahydrofuran was stirred while 6.2 g (0.08 mole) of 40% aqueousmethylamine was added. The reaction mixture was exothermic and wasallowed to cool to ambient temperature while stirring for 18 hr. Thereaction mixture was diluted with 200 ml of ice water and the oildroplets which separated quickly crystallized. Filtration yielded 6.6 gof crude product. The solid was dissolved in 100 ml of methylenechloride, treated with 15 g of silica gel and stirred for 2 hr. Thesilica gel was removed by filtration and washed with 200 ml of 50/50ethyl acetatemethylene chloride. The combined filtrates wereconcentrated on a rotary evaporator, yielding 5.8 g of solid residue.The solid was recrystallized by dissolving in 22 ml of acetone andadding 88 ml of isopropyl ether. The volume was reduced to 40 ml byboiling under nitrogen atmosphere and upon cooling the productcrystallized. Filtration yielded 2.95 (66.7%) of white crystals, m.p.140°-142° C.

Analysis: Calculated for C₁₁ H₁₃ FN₂ O₂ : C,58.92; H,5.84; N,12.49

Found: C,59.01; H,5.87; N,12.37

EXAMPLE 74 3-(4-Fluorophenoxy)-1-azetidinecarboxamide

A solution of 5.52 g (0.022 mole) of crude3-(4-fluorophenoxy)-1-azetidine carbonyl chloride in 20 ml oftetrahydrofuran was treated with 10 ml of concentrated ammoniumhydroxide while stirring. The exothermic reaction mixture was stirredfor 18 hr as it cooled to ambient temperature. The reaction mixture wasdiluted with 400 ml of ice water to produce a phase separation. Uponstanding, the oily phase solidified and was collected by filtrationyielding 12.5 g of crude wet product. Recrystallization from aqueousethanol after charcoal treatment produced an oil which slowlycrystallized. The sample was recrystallized from methylene chloride,yield 1.6 g (35%) of amorphous-like powder, m.p. 185°-188° C.

Analysis: Calculated for C₁₀ H₁₁ FN₂ O₂ : C,57.14; H,5.28; N,13.33

Found: C,57.33; H,5.31; N,12.93

EXAMPLE 75 3-(4-Fluorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A stirred and cooled (32° C.) mixture of 5.52 g (0.022 mole) of crude3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) ofpotassium carbonate in 30 ml of tetrahydrofuran was treated with 1.5 g(0.02 mole) of 3-aminopropylene. The reaction mixture was stillexothermic and was stirred for 5 hr as it cooled to ambient temperature.The reaction mixture was diluted with 200 ml of water to produce an oilphase separation. The oil portion was dissolved by extracting with 2×50ml of benzene. The extracts were combined, dried over magnesium sulfateand concentrated in vacuo to yield 8.14 g of orange-red oil. The oilpartially crystallized from benzene-ligroin with charcoal treatment,yielding first a reddish oil followed by a crystalline product, Thetotal material was concentrated in vacuo to yield 7.45 g of amber-redoil. This oil solidified and was repeatedly triturated with isopropylether until only a red oil residue remained. The isopropyl etherportions were repeatedly cooled to the crystallization of residue,decanted from residue and heated to reduce volume until only a strawcolored isopropyl ether solution remained. Upon cooling of this solutionthe title product crystallized and yielded 2.3 g (42.3%) of whitecrystalline product, m.p. 92°-94° C.

Analysis: Calculated for C₁₃ H₁₅ FN₂ O₂ : C,62.39; H,6.04; N,11.19

Found: C,62.35; H,6.04; N,11.20

EXAMPLE 76 3-(4-Fluorophenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A mixture of 5.52 g (0.022 mole) of crude3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) ofpotassium carbonate in 30 ml of tetrahydrofuran was cooled in an icebath and while stirring treated with 1.1 g (0.02 mole) of propargylamineadded dropwise. After stirring for 5 hr, the reaction mixture wasdiluted with 250 ml of water and the resulting solid collected byfiltration to yield 8.67 g of wet product. Recrystallization fromacetone after filtration to remove some amorphous material, gave a tackysolid. A second recrystallization from benzene after treating withcharcoal yielded 2.7 g (50%) of beige crystals, m.p. 106°-108° C.

Analysis: Calculated for C₁₃ H₁₃ FN₂ O₂ : C,62.90; H,5.28; N,11.28

Found: C,62.81; H,5.28; N,11.21

EXAMPLE 77 3-(3,4-Dichlorophenoxy)-N-methyl-1-azetidinecarboxamide

A solution of 5.6 g (0.02 mole) of3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was stirred while 5 ml (0.06 mole) of 40% aqueousmethylamine was added slowly, stirring was continued for 18 hr. Thereaction mixture was diluted with 200 ml of ice water, and the solidwhich formed was collected by filtration, 6.9 g. The crude wet solid wasrecrystallized from ethanol/water to yield 3.65 g (66.3%) ofgreenish-gray plate-like crystals, m.p. 158°-159° C.

Analysis: Calculated for C₁₁ H₁₂ Cl₂ N₂ O₂ : C,48.02; H,4.40; N,10.18

Found: C,48.18; H,4.39; N,10.00

EXAMPLE 78 3-(3,4-Dichlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A stirred solution of 5.6 g (0.02 mole) of3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 3.0 g (0.04 mole) of propenylamine, andstirring was continued for 18 hr. The reaction mixture was diluted with200 ml of ice water, and the solid which formed was collected byfiltration, yielding 7.1 g of crude wet product. Recrystallization frombenzene/ligroin yielded 3.95 g (65.6%) of white crystals, m.p. 98°-99°C.

Analysis: Calculated for C₁₃ H₁₄ Cl₂ N₂ O₂ C,51.85; H,4.69; N,9.30

Found: C,51.94; H,4.67; N,9.27

EXAMPLE 79 3-(3,4-Dichlorophenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A stirred mixture of 5.6 g (0.02 mole) of3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride and 3 g (0.02 mole)of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1g (0.02 mole) of 2-propynylamine added dropwise from a needle syringethen stirred for an additional 18 hr. The reaction mixture was dilutedwith 200 ml of water and the resulting solid collected by filtration toyield 7.1 g of crude product. Recrystallization from isopropyl etheryielded 4.98 g (83.2%) of pale beige crystals, m.p. 119°-121° C.

Analysis: Calculated for C₁₃ H₁₂ Cl₂ N₂ O₂ : C,52.20; H,4.04; N,9.36

Found: C,52.20; H,3.96; N,9.19

EXAMPLE 80 3-(4-Chlorophenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A stirred mixture of 7.4 g (0.03 mole) of3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride and 4.5 g (0.03 mole)of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.7g (0.03 mole) of 2-propynylamine added dropwise from a needle andsyringe. After stirring for 16 hr, the reaction mixture was diluted with400 ml of water and the resulting tan solid was collected by filtration,yielding 7.7 g of crude product. Repeated triturations of the crudeproduct with hot benzene gave upon combining and cooling 1.2 g (15.2%)of tan powder, m.p. 120°-122° C.

Analysis: Calculated for C₁₃ H₁₃ ClN₂ O₂ : C,58.99; H,4.95 N,10.58C,59.12; H,4.83; N,10.52

EXAMPLE 81 3-(3-Bromophenoxy)-1-azetidinecarboxamide

A solution of 5.8 g (0.02 mole) of3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was stirred at ambient temperature while 4 ml (0.06mole) of 57% ammonium hydroxide was slowly added. After stirring for 48hr, the reaction mixture was diluted with 100 ml of water and theresulting solid collected by filtration (5 g). Recrystallization fromisopropanol yielded 3.7 g (59%) of fine beige crystals, m.p. 188°-189°C.

Analysis: Calculated for C₁₀ H₁₁ BrN₂ O₂ : C,44.30; H,4.09; N,10.33

Found: C,44.06; H,4.00; N,10.25

EXAMPLE 82 3-(3-Bromophenoxy)-N-methyl-1-azetidinecarboxamide

A stirred solution of 5.8 g (0.02 mole) of3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueousmonomethylamine. After stirring for 48 hr, the reaction mixture wasdiluted with 100 ml of water and the solid which formed was collected byfiltration (6.0 g). Recrystallization from benzene yielded 2.0 g (35.1%)of tan crystals, m.p. 134°-135° C.

Analysis: Calculated for C₁₁ H₁₃ BrN₂ O₂ : C,46.34; H,4.60; N,9.82

Found: C,46.09; H,4.51; N,9.86

EXAMPLE 83 3-(3-Bromophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A stirred solution of 5.8 g (0.02 mole) of3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 2.85 g (0.05 mole) of 2-propenylamine.After stirring for 48 hr, the reaction mixture was diluted with 100 mlof water and the reddish oil which separated solidified upon standing.The solids were collected by filtration, 5.9 g. Upon repeatedtrituration with boiling isopropyl ether, the combined triturates uponcooling yielded 4 g (64.4%) of fine white crystals, m.p. 90°-92° C.

Analysis: Calculated for C₁₃ H₁₅ BrN₂ O₂ : C,50.18; H,4.86; N,9.00

Found: C,50.19; H,4.90; N,9.09

EXAMPLE 84 3-(3,4-Dichlorophenoxy)-1-azetidinecarboxamide

A solution of 5.6 g (0.02 mole) of3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated while stirring with 3 ml (0.04 mole) of 57%ammonium hydroxide. After stirring for 18 hr, the reaction mixture wasdiluted with 200 ml of water and the solid which separated was collectedby filtration, 6.6 g. Recrystallization from ethanol-water yielded 3.0 gof white granular crystals, m.p. 179°-184° C. A second recrystallizationfrom isopropanol yielded 2.7 g (51.7%) of fine white crystals, m.p.185°-187° C.

Analysis: Calculated for C₁₀ H₁₀ Cl₂ N₂ O: C,46.00; H,3.86; N,10.73

Found: C,46.31; H,3.89; N,10.67

EXAMPLE 85 3-(4-Chlorophenoxy)-1-azetidinecarboxamide

A solution of 5 g (0.02 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonylchloride in 20 ml of tetrahydrofuran was stirred while 4 ml (0.06 mole)of 57% ammonium hydroxide was added all at once. After stirring for 18hr, the reaction mixture was diluted with 200 ml of water and the solidwhich separated was collected by filtration, 10.5 g. Recrystallizationfrom isopropanol yielded 2.4 g (52.9%) of gray crystalline powder, m.p.187°-188° C.

Analysis: Calculated for C₁₀ H₁₁ ClN₂ O₂ : C,52.99; H,4.89; N,12.36

Found: C,52.90; H,4.85; N,12.30

EXAMPLE 86 3-(4-Chlorophenoxy)-N-methyl-1-azetidinecarboxamide

A stirred solution of 5 g (0.02 mole) of3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueousmonomethylamine. After stirring for 18 hr, the reaction mixture wasdiluted with 200 ml of water and the solid which separated was collectedby filtration, 5.7 g. Recrystallization from benzene-ligroin wasaccomplished by adding magnesium sulfate to absorb the water whichseparated from the wet product. After filtering and cooling the hotfiltrate, the precipitated solid was collected by filtration to yield4.1 g (85.2%) of white crystals, m.p. 144°-145° C.

Analysis: Calculated for C₁₁ H₁₃ ClN₂ O₂ : C,54.89; H,5.44; N,11.64

Found: C,54.89; H,5.43; N,11.65

EXAMPLE 87 3-(4-Chlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A stirred solution of 5 g (0.02 mole) of3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran with 4.5 g (0.06 mole) of 2-propenylamine. Afterstirring for 18 hr, the reaction mixture was diluted with 200 ml ofwater and the solid precipitate which formed after stirring for 5 hr wascollected by filtration, 7.7 g. This product was dissolved by successivetrituration with boiling isopropyl ether. The combined triturates weredecanted from a thin film of oil which formed as it cooled. The cooledisopropyl ether triturates yielded 2.9 g (54.4%) of white crystallineproduct, m.p. 98°-99° C.

Analysis: Calculated for C₁₃ H₁₅ ClN₂ O₂ : C,58.54; H,5.67; N,10.50

Found: C,58.57; H,5.66; N,10.49

EXAMPLE 88 3-(3-Bromophenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A stirred mixture of 5.8 g (0.02 mole) of3-(3-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) ofpotassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g(0.02 mole) of 2-propynylamine added dropwise from a needle and syringe.A piece of ice was added and stirring was continued for 42 hr. The solidresidue which remained was stirred with 100 ml of water then filtered,yielding 5.3 g of crude product. Recrystallization from ethanol yielded4.0 g of fine beige crystals, m.p. 145°-147° C. After drying at 100° C.in vacuo, m.p. was 146°-147° C. (64.7%).

Analysis: Calculated for C₁₃ H₁₃ BrN₂ O₂ : C,50.51; H,4.24; N,9.06

Found: C,50.31; H,4.27; N,9.00

EXAMPLE 89 3-(4-Bromophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A stirred solution of 5.8 g (0.02 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamineand stirring continued for 18 hr. The reaction mixture was diluted with200 ml of water and the oil which separated slowly solidified. Aftercollecting the solid by filtration, it was triturated 4 times withboiling isopropyl ether. The combined triturates upon cooling yielded3.7 g (59.5%) of white crystals, m.p. 100°-101° C.

Analysis: Calculated for C₁₃ H₁₅ BrN₂ O₂ : C,50.18; H,4.86; N,9.00

Found: C,50.20; H,4.90; N,9.02

EXAMPLE 90 3-(4-Bromophenoxy)-1-azetidinecarboxamide

A stirred solution of 5.8 g (0.02 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 3.8 g (4 ml) (0.06 mole) of 57%ammonium hydroxide. After stirring for 18 hr, the reaction mixture wasdiluted with 200 ml of water and the solid which separated was collectedby filtration, 5.3 g. Recrystallization from ethanol-water yielded 4.75g (87.6%) of fine white crystals, m.p. 193°-194° C.

Analysis: Calculated for C₁₀ H₁₁ BrN₂ O₂ : C,44.30; H,4.09; N,10.33

Found: C,44.46; H,4.10; N,10.39

EXAMPLE 91 3-(4-Bromophenoxy)-N-methyl-1-azetidinecarboxamide

A stirred solution of 5.8 g (0.02 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueousmonomethylamine and stirring continued for 18 hr. The reaction mixturewas diluted with 200 ml of water and the solid which separated wascollected by filtration, 5.7 g. Recrystallization from ethanol-wateryielded 4.9 g (85.9%) of fine white crystals, m.p. 135°-137° C.

Analysis: Calculated for C₁₁ H₁₃ BrN₂ O₂ : C,46.34; H,4.60; N,9.82

Found: C,46.49; H,4.62 N,9.92

EXAMPLE 92 3-(4-Bromophenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A stirred mixture of 5.8 g (0.02 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) ofpotassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g(0.02 mole) of 2-propynylamine added dropwise from a needle and syringe.After stirring for 30 min, approximately 1 g of ice was added andstirring continued for 18 hr. The reaction mixture was diluted with 200ml of water and the solid which separated was collected by filtration,6.1 g. After drying, recrystallization from benzene-ligroin yielded 4.2g (67.9%) of fine white crystals, m.p. 120°-122° C.

Analysis: Calculated for C₁₃ H₁₃ BrN₂ O₂ : C,50.51; H,4.24; N,9.06

Found: C,50.67; H,4.26 N,9.10

EXAMPLE 93 3-(3-Methylphenoxy)-1-azetidinecarboxamide

A stirred solution of 3.92 g (0.01 mole) of crude (57.59%)3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahydrofuran was treated with 1.9 g (2 ml) (0.03 mole) of 57%ammonium hydroxide. After stirring for 18 hr, the reaction mixture wasdiluted with 200 ml of water. The oil which separated solidified onstanding, (3.2 g), and was recrystallized from isopropanol, yielding 1 g(50%) of fine white crystals, m.p. 167°-168° C.

Analysis: Calculated for C₁₁ H₁₄ N₂ O₂ : C,64.06; H,6.84; N,13.58

Found: C,64.15; H,6.88; N,13.24

EXAMPLE 94 3-(3-Methylphenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A stirred solution of 3.92 g (0.01 mole) of crude (57.59%)3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahydrofuran was treated with 2.25 g (0.03 mole) of 2-propenylamine.After stirring for 18 hr, the reaction mixture was diluted with 200 mlof water and a reddish oil separated. A sample of this oil crystallizedat -70° C. and was used to seed the oil residue. The resulting solid wascollected by filtration to yield 3.6 g which was recrystallized frombenzene-ligroin yielding, after charcoal treatment, 1.53 g (62.2%) ofpale beige crystals, m.p. 95°-96° C.

Analysis: Calculated for C₁₄ H₁₈ N₂ O₂ : C,68.27; H,7.37; N,11.37

Found: C,68.10; H,7.34; N,10.93

EXAMPLE 95 3-(3-Methylphenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A stirred mixture of 3.92 g (0.01 mole) of crude (57.59%)3-(3-methylphenoxy)-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole)of potassium carbonate in 15 ml of tetrahydrofuran was treated with 0.55g (0.01 mole) of 2-propynylamine added dropwise from a needle andsyringe. After 10 min, approximately 1 g of ice was added and stirringcontinued for 18 hr. The reaction mixture was diluted with 200 ml ofwater and the oil which separated slowly solidified. The precipitatedsolid was collected by filtration to yield 4.7 g of crude wet product.After air drying, the solid was recrystallized from benzene-ligroin toyield 1.78 g (72.9%) of fine white crystals, m.p. 140°-142° C.

Analysis: Calculated for C₁₄ H₁₆ N₂ O₂ : C,68.83; H,6.60; N,11.47

Found: C,68.58; H,6.60; N,11.22

EXAMPLE 96 3-(3-Methoxyphenoxy)-N-(2-propenyl)-1-azetidinecarboxamide

A solution of 4.85 g (0.02 mole) of3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamineand stirred for 17 hr, diluted with 200 ml of water and extracted with3×50 ml of methylene chloride. The combined extracts were dried thenconcentrated in vacuo to yield 4.03 g of oil residue. The residue waschromatographed on a spinning TLC plate (chromatotron) in 3 portions (3runs) using a ethyl acetate/methylene chloride gradient. The 4thfraction of each run was combined and concentrated in vacuo to yield awhite solid (1.2 g), which was recrystallized from benzene-ligroinyielding 0.94 g (18%) of fine white crystals, m.p. 121°-123° C.

Analysis: Calculated for C₁₄ H₁₈ N₂ O₃ : C,64.11; H,6.92 N,10.68

Found: C,64.39; H,6.78 N,10.45

EXAMPLE 97 3-(3-Methoxyphenoxy)-N-(2-propynyl)-1-azetidinecarboxamide

A mixture of 4.85 g (0.02 mole) of3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole)of anhydrous potassium carbonate in 20 ml of tetrahydrofuran was stirredwhile 1.1 g (0.02 mole) of 2-propynylamine was added dropwise from aneedle and syringe. After stirring for 30 min, a small piece of ice wasadded and stirring continued for 17 hr. The reaction mixture was dilutedwith 200 ml of water then extracted with 3×50 ml of methylene chloride.The combined extracts were dried by passing through Whatman phaseseparating paper then concentrated in vacuo to an oily residue (3.73 g).This residue was dissolved in 30 ml of methylene chloride andchromatographed in three portions (3 runs) on a spinning TLC plate(chromatotron) with an ethyl acetate-methylene chloride gradient from10%-100% ethyl acetate. A white solid (1.8 g) was obtained onconcentration of the product fractions. Recrystallization from isopropylether yielded 0.93 g (17.9%) of white crystalline product, m.p.121°-123° C.

Analysis: Calculated for C₁₄ H₁₆ N₂ O₃ : C,64.60; H,6.20; N,10.76

Found: C,64.51; H,6.30; N,10.48

EXAMPLE 98 N-Methyl-3-(3-methylphenoxy)-1-azetidinecarboxamide

A stirred solution of 3.92 g (0.01 mole) of3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahydrofuran was treated with 2.4 g (0.03 mole) of 40% aqueousmonomethylamine and stirring continued for 17 hr. The reaction mixturewas diluted with 200 ml of water. The reddish oil residue was cooled to-78° C. whereupon it crystallized (4.28 g). Recrystallization frombenzene-ligroin gave 400 mg of fine white crystals, m.p. 143°-144° C.Addition of more ligroin yielded an additional 800 mg of "cream" coloredcrystalline product, m.p. 138°-142° C. The two fractions were combinedand recrystallized from ethanol-isopropyl ether, yielding 600 mg (27.3%)of fine white crystals, m.p. 143°-144° C.

Analysis: Calculated for C₁₂ H₁₆ N₂ O₂ : C,65.43; H,7.32; N,12.72

Found: C,65.40; H,7.37; N,12.72

EXAMPLE 99 3-Phenoxy-1-azetidinecarboxamide

A stirred slurry of 7 g (0.03 mole) of 3-phenoxyazetidine oxalate [1:1]in 100 ml of acetone was treated with 5.3 g (0.05 mole) of nitroureathen after 30 min, treated with 5 ml of water and 5 ml of triethylamine.After stirring for 8 hr, the reaction mixture was diluted with 125 ml ofwater and stirred until a fine white crystalline solid precipitated.Filtration yielded 3.85 g, m.p. 179°-186° C. The solid wasrecrystallized from tetrahydrofuran to yield 1.3 g (22.5%) of fine whitecrystals, m.p. 195°-196° C.

Analysis: Calculated for C₁₀ H₁₂ N₂ O₂ : C,62.49; H,6.29; N,14.57

Found: C,62.50; H,6.29; N,14.59

EXAMPLE 1001-[3-(4-Bromophenoxy)-1azetidinylcarbonyl]-4-phenylpiperazine

A solution of 2.9 g (0.01 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahydrofuran was treated while stirring with 1.6 g (0.01 mole) of1-phenylpiperazine added all at once, a solid formed instantaneously andafter stirring for 2 hr, the reaction mixture was diluted with 200 ml ofwater, the solid did not dissolve. The solid was removed by filtrationand when triturated with chloroform, all but about 1 g of soliddissolved. The chloroform solution was dried over magnesium sulfate thenconcentrated in vacuo. The oily residue crystallized when trituratedwith ligroin. Recrystallization from benzene/ligroin yielded 2.0 g(48.1%) of fine white crystals, m.p. 160°-161° C.

Analysis: Calculated for C₂₀ H₂₂ BrN₃ O₂ : C,57.70; H,5.33; N,10.09

Found: C,57.72; H,5.31; N,10.01

EXAMPLE 1011-[3-(4-Bromophenoxy)-1-azetidinylcarbonyl]-4-(phenylmethyl)piperazine

A solution of 2.9 g (0.01 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahyfrofuran was treated while stirring with the dropwise addition of1.8 g (0.01 mole) of 1-benzylpiperazine. After stirring for 2 hr, thereaction mixture was diluted with water (200 ml) and 1.4 g of potassiumcarbonate was added. The solid precipitate was collected by filtration(5.2 g). Recrystallization from benzene/ligroin yielded 3.4 g (79.1%) ofwhite crystals, m.p. 133°-135° C.

Analysis: Calculated for C₂₁ H₂₄ BrN₃ O₂ : C,58.61; H,5.62; N,9.76

Found: C,58.77; H,5.62; N,9.65

EXAMPLE 1021-[3-(4-Bromophenoxy)-1-azetidinylcarbonyl]-4-methylpiperazine fumarate[1:1]

A solution of 2.9 g (0.01 mole) of3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml oftetrahydrofuran was treated while stirring with 1 g (0.01 mole) of1-methylpiperazine and stirred for 2 hr. The paste-like slurry wasdiluted with water and the solid was collected by filtration (4 g, wet).Recrystallization from benzene/ligroin yielded 3.0 g of whitecrystalline product, m.p. 91°-95° C. The solid and 1.16 g of fumaricwere dissolved in isopropanol by boiling until a clear solution wasobtained. Upon cooling, the precipitated salt was collected byfiltration to yield 3 g (63.8%) of fine white crystals, m.p. 197°-198°C.

Analysis: Calculated for C₁₅ H₂₀ BrN₃ O₂.C₄ H₄ O₄ : C,48.52; H,5.14;N,8.93

Found C,48.49; H,5.14; N,8.93

EXAMPLE 1031-[3-(3-Bromophenoxy)-1-azetidinylcarbonyl]-4-methylpiperazine fumarate[1:1]

A stirred solution of 2.9 g (0.01 mole) of3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of methylenechloride was treated with 2 g (0.02 mole) of 1-methylpiperazine. Afterstirring for 18 hr, the reaction mixture was diluted with 200 ml ofwater and stirred an additional 1 hr. The methylene chloride portion wasseparated, dried, and concentrated in vacuo to yield 4.84 g of amberoil. A solution of the residue in 50 ml of ethyl ether was added to ahot solution of 1.16 g of fumaric acid in 25 ml of isopropanol. Uponcooling, the precipitated solid was collected by filtration to yield 2.4g (51%) of granular crystals, m.p. 159°-161° C.

Analysis: Calculated for C₁₅ H₂₀ BrN₃ O₂.C₄ H₄ O₄ : C,48.52; H,5.14;N,8.93

Found C,48.42; H,5.17; N,8.81

EXAMPLE 1041-[3-(4-Fluorophenoxy)-1-azetidinylcarbonyl]-4-methylpiperazine fumarate[1:1]

A stirred solution of 2.3 g (0.01 mole) of3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of methylenechloride was treated with 2 g (0.02 mole) of 1-methylpiperazine. Afterstirring for 18 hr, the reaction mixture was diluted with 200 ml ofwater and stirred an additional 1 hr. The methylene chloride portion wasseparated and the aqueous portion extracted with 50 ml of methylenechloride. The methylene chloride portions were combined, dried andconcentrated in vacuo to yield 2.53 g of oil residue. The oil residue in10 ml of acetone was added to 1.16 g of fumaric acid dissolved in 50 mlof boiling isopropanol. Upon cooling, the precipitated solid wascollected by filtration to yield 2.8 g (68.4%) of white granularcrystals, m.p. 173°-174° C.

Analysis: Calculated for C₁₅ H₂₀ FN₃ O₂.C₄ H₄ O₄ : C,55.74; H,5.91;N,10.26

Found: C,55.67; H,5.91; N,10.09

EXAMPLE 1051-[3-(4-Fluorophenoxy)-1-azetidinylcarbonyl]-4-phenylpiperazine

A stirred solution of 2.3 g (0.01 mole) of3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of methylenechloride was treated with 2.6 g (0.02 mole) of 1-phenylpiperazine. Afterstirring for 18 hr, the reaction mixture was diluted with 200 ml ofwater and stirred an additional 1 hr. The methylene chloride portion wasseparated and the aqueous portion extracted with 25 ml of methylenechloride. The combined methylene chloride portions were dried, andconcentrated in vacuo to yield an oil residue (3.9 g). The oil residuesolidified from isopropanol and was recrystallized by adding methanol toredissolve then ethyl ether to effect crystallization. Upon cooling, thelarge precipitated crystals were collected by filtration to yield 2 g(63.3%), m.p. 124°-125° C. An additional 2.5 g of crude tan product wasobtained by concentrating the filtrate.

Analysis: Calculated for C₂₀ H₂₂ FN₃ O₂ : C,67.59; H,6.24 N,11.82

Found: C,67.62; H,6.28; N,11.75

EXAMPLE 1061-[3-(4-Fluorophenoxy)-1-azetidinylcarbonyl]-4-(phenylmethyl)piperazine

A stirred solution of 6.9 g (0.03 mole) of3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 60 ml of methylenechloride was treated with 10.8 g (0.06 mole) of 1-benzylpiperazine,added dropwise. After stirring for 18 hr, the reaction mixture wasdiluted with 200 ml of water and stirred for an additional 1 hr. Themethylene chloride portion was separated and the aqueous portion wasextracted with 2×25 ml of methylene chloride. The methylene chlorideportions were combined, dried and concentrated in vacuo, yielding 12 gof oil residue. This oil solidified when triturated with ligroin and wasrecrystallized from benzene/ligroin to yield 10.1 (91%) of tan crystals.A 500 mg portion was recrystallized from benzene/ligroin to yield 250 mgof fine white crystals, m.p. 109°-111° C.

Analysis: Calculated for C₂₁ H₂₄ FN₃ O₂ : C,68.27; H,6.55; N,11.37

Found: C,68.29; H,6.68; N,11.27

EXAMPLE 1071-[3-(4-Fluorophenoxy)-1-azetidinylcarbonyl]-4-(phenylmethyl)piperazinefumarate [1:1]

A 2.5 g portion of1-[3-(4-fluorophenoxy)-1-azetidinylcarbonyl]-4-(phenylmethyl)piperazinewas dissolved in isopropanol and treated with 0.8 g of fumaric aciddissolved in 2.5 ml of hot isopropanol. Upon cooling, the precipitatewas collected by filtration, yielding 3 g (91.3%) of fine whitecrystals, m.p. 183°-184° C.

Analysis: Calculated for C₂₁ H₂₄ FN₃ O₂.C₄ H₄ O₄ : C,61.85; H,5.81;N,8.66

Found D,61.66; H,5.93; N,8.59

EXAMPLE 1081-[3-(3,4-Dichlorophenoxy)-1-azetidinylcarbonyl]-4-methylpiperazinefumarate [1:1]

A stirred solution of 2.8 g (0.01 mole) of crude3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml oftetrahydrofuran was treated with 1 g (0.01 mole) of 1-methylpiperazinethen with 1.42 g (0.01 mole) of potassium carbonate. After stirring for30 min, approximately 2 g of ice was added and stirring continued for 18hr. The reaction mixture was diluted with 200 ml of water and an oilseparated. Upon standing, this oil solidified and was collected byfiltration, yielding 3.3 g of crude product. The solid was dissolved in20 ml of isopropanol and treated with 1.16 g of fumaric acid dissolvedin 25 ml of boiling isopropanol. The volume was reduced to 30 ml byheating under a stream of nitrogen and upon cooling, the precipitatedsalt was collected by filtration, yielding 1.35 g (95.9%) of whitecrystals, m.p. 187°-188° C.

Analysis: Calculated for C₁₅ H₁₉ Cl₂ N₃ O₂.C₄ H₄ O₄ : C,49.58; H,5.06;N,9.13

Found C,49.57; H,5.21; N,8.96

EXAMPLE 1091-[3-(3,4-Dichlorophenoxy)-1-azetidinylcarbonyl]-4-(phenylmethyl)piperazinefumarate [1:1]

A stirred solution of 2.8 g (0.01 mole) of crude3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml oftetrahydrofuran was treated with 1.8 g (0.01 mole) of 1-benzylpiperazinethen with 1.4 g (0.01 mole) of potassium carbonate. After stirring for30 min, approximately 2 g of ice was added and stirring continued for 18hr. The reaction mixture was diluted with 200 ml of water. Afterstirring for 24 hr, the oil which separated had solidified and wascollected by filtration (4.8 g). The solid, dissolved in 20 ml ofisopropanol, was treated with 1.16 g of fumaric acid dissolved in 25 mlof boiling isopropanol. Upon cooling, the precipitate was collected toyield 2.4 g (55%) of fine white crystalline product, m.p. 193°-195° C.

Analysis: Calculated for C₂₁ H₂₃ Cl₂ N₃ O₂.C₄ H₄ O₄ : C,55.98; H,5.07;N,7.83

Found C,55.96; H,5.10; N,7.79

EXAMPLE 1101-Phenyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazine

A mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran wasstirred for 10 min then 1.6 g (0.01 mole) of 1-phenylpiperazine wasadded. After stirring for 30 min, approximately 2 g of ice was added andstirring continued for 18 hr. The reaction mixture was diluted with 200ml of water and the oil which separated was extracted into methylenechloride (2×50 ml), dried and concentrated in vacuo to yield 5.1 g ofcrude dark yellow oil, which solidified when cooled to -78° C.Recrystallization from isopropyl ether yielded 2.2 g (54.3%) of paleyellow crystals, m.p. 93°-94° C.

Analysis: Calculated for C₂₁ H₂₂ F₃ N₃ O₂ : C,62.22; H,5.47; N,10.37

Found: C,62.30; H,5.54; N,10.37

EXAMPLE 1111-(2-Pyridinyl)-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazine

A mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.43 g(0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran wastreated, while stirring, with 1.6 g (0.01 mole) of1-(2-pyridyl)piperazine. After 30 min, approximately 2 g of ice wasadded and stirring continued for 18 hr. The reaction mixture was dilutedwith 200 ml of water and upon stirring, transparent crystals formed.After 24 hr the precipitate was collected by filtration (4 g) andrecrystallized from isopropyl ether with a trace of acetone to yield 2.6g (64%) of silver plate-like crystals, m.p. 111°-112° C.

Analysis: Calculated for C₂₀ H₂₁ F₃ N₄ O₂ : C,59.11; H,5.21; N,13.79

Found: C,59.20; H,5.29; N,13.76

EXAMPLE 1124-Phenyl-1-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperidine

A mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran wasstirred for 10 min then treated with 1.6 g (0.01 mole) of4-phenylpiperidine. After stirring for 30 min, approximately 2 g of icewas added and stirring continued for 18 hr. The reaction mixture wasdiluted with 200 ml of water and the oil which separated was extractedinto methylene chloride (2×50 ml). The extracts were combined, dried andconcentrated in vacuo to yield 4.95 g of crude oil which solidified whencooled to -78° C. Recrystallization from isopropyl ether yielded 1.5 g(37%) of coarse white crystals, m.p. 72°-74° C.

Analysis: Calculated for C₂₂ H₂₃ F₃ N₂ O₂ : C,65.34; H,5.73; N,6.93

Found: C,65.41; H,5.80; N,6.94

EXAMPLE 113 1,2,3,6-Tetrahydro-4-phenyl-1-[1-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]pyridine

A mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 2.8 g(0.02 mole) of potassium carbonate in 25 ml of tetrahydrofuran wasstirred for 10 min and treated with 2 g (0.01 mole)4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride. After stirring for 30min, approximately 2 g of ice was added and stirring continued for 18hr. The reaction mixture was diluted with 200 ml of water and the oilwhich separated was extracted into methylene chloride (2×50 ml). Theextracts were combined, dried and concentrated in vacuo to yield 4.5 gof orange-yellow oil which solidified when cooled to -78° C.Recrystallization from isopropyl ether after charcoaling yielded 2.6 g(65%) of fine white crystals, m.p. 100°-102° C.

Analysis: Calculated for C₂₂ H₂₁ F₃ N₂ O₂ : C,65.66; H,5.26; N,6.96

Found: C,65.71; H,5.30; N,6.96

EXAMPLE 1141-[3-(3,4-Dichlorophenoxy)-1-azetidinylcarbonyl]-4-(2-pyridinyl)piperazine

A stirred solution of 2.8 g (0.01 mole) of3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml oftetrahydrofuran was treated in turn with 1.6 g (0.01 mole) of1-(2-pyridyl)piperazine and 1.4 g (0.01 mole) of potassium carbonate.After 30 min, a solid had precipitated which dissolved whenapproximately 2 g of ice was added. After stirring for 18 hr, thereaction mixture was diluted with 200 ml of water and a paste-like solidseparated which was filtered to yield 3.3 g of crude product. Afterseveral attempts to recrystallization from methyl isobutyl ketone, itwas recrystallized from acetonitrile to yield 1.25 g (30.7%) of finewhite crystals, m.p. 153.5°-154.5° C.

Analysis: Calculated for C₁₃ H₂₀ Cl₂ N₄ O₂ : C,56.03; H,4.95; N,13.76

Found: C,55.96; H,4.96; N,13.77

EXAMPLE 1151-[3-(3-Bromophenoxy)-1-azetidinylcarbonyl]-4-(phenylmethyl)piperazinefumarate [1:1]

A stirred solution of 2.9 g (0.01 mole) of3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of methylenechloride was treated with 3.6 g (0.02 mole) of 1-benzylpiperazine addeddropwise. After stirring for 16 hr, the reaction mixture was dilutedwith 200 ml of water and the methylene chloride layer separated, driedover magnesium sulfate, and concentrated in vacuo to yield a pale amberoil (8.2 g). This residue was dissolved in diethyl ether and treatedwith 1.2 g of fumaric acid dissolved in 75 ml of boiling isopropylalcohol. Upon cooling and filtering, the precipitated solid yielded 3.65g of fine white crystals, m.p. 195°-196° C. Mass spectra data indicatethe solid was mainly the fumarate salt of 1-benzylpiperazine. Thefiltrate was converted to the free base by addition of ammoniumhydroxide and extraction with methylene chloride. The extracts weredried and concentrated in vacuo. The residue obtained waschromatographed on a 120 g silica gel column by first eluting withmethylene chloride to wash the column then with a methanol/methylenechloride gradient from 0.5% to 2% methanol. The fractions (2-200 ml)which contained the desired product by TLC were combined andconcentrated in vacuo to yield 3.5 g of yellow oil. The oil in 25 ml ofisopropanol was treated with 1.2 g of fumaric acid and heated until aclear solution was obtained. The volume was reduced to 10 ml undernitrogen and 25 ml of isopropyl ether was added. Upon cooling,filtration yielded 3.3 g (45.1%) of fine white crystals, m.p. 164°-165°C.

Analysis: Calculated for C₂₁ H₂₄ BrN₃ O₂.C₄ H₄ O₄ : C,54.95; H,5.17;N,7.69

Found: C,54.94; H,5.16; N,7.70

EXAMPLE 1164-(4-Chlorophenyl)-1-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]-4-piperidinol

A stirred mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran wastreated with 2 g (0.01 mole) of 4-(4-chlorophenyl)-4-hydroxypiperidineadded in small portions. After stirring for 30 min, a few pieces of icewere added and stirring continued for 16 hr. The reaction mixture wasdiluted with 200 ml of water and the oil which separated was extractedinto methylene chloride (2×50 ml). The combined extracts were dried overmagnesium sulfate and concentrated in vacuo to give a water-like oil(5.16 g). A crystalline solid was obtained by cooling to -78° C. andrecrystallization was accomplished by dissolving the residue in 5 ml ofacetone and 75 ml of isopropyl ether and reducing the volume undernitrogen to 40 ml. Upon cooling, filtration yielded 3.6 g (79.1%) offine white crystals, m.p. 127°-128.5° C.

Analysis: Calculated for C₂₂ H₂₂ F₃ ClN₂ O₃ : C,58.09; H,4.88 N,6.16

Found: C,57.88; H,4.90; N,6.08

EXAMPLE 117

When in the procedure of Example 37 and utilizing Method B, substitutingthe following for 1-propylpiperazine:

a) 1-(2-methoxyphenyl)piperazine hydrochloride,

b) 1-(α,α,α-trifluoro-m-tolyl)piperazine,

c) 2,6-dimethylmorpholine,

d) 3,5-dimethylmorpholine, and

e) morpholine

there are obtained:

a)1-(2-methoxyphenyl)-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazinefumarate,

b)1-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]-4-[3-(trifluoromethyl)phenyl]piperazinefumarate,

c)2,6-dimethyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]morpholinefumarate,

d)3,5-dimethyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]morpholinefumarate, and

e) 4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]morpholinefumarate.

EXAMPLE 1182-[4-[3-[3-(Trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]-1-piperazinyl]pyrimidine

A stirred mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran wastreated with 1.6 g (0.01 mole) of 1-(2-pyrimidyl)piperazine addeddropwise. After stirring for 30 min, a few pieces of ice were added andstirring continued for 16 hr. The reaction mixture was diluted with 200ml of water and the oil which separated slowly crystallized.Recrystallization from isopropyl ether yielded 2.7 g (66.3%) of finewhite crystals, m.p. 127°-128° C.

Analysis: Calculated for C₁₉ H₂₀ F₃ N₅ O₂ : C,56.20; H,4.95; N,17.19

Found: C,56.01; H,4.94; N,17.15

EXAMPLE 1191-(Phenylmethyl)-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]piperazinefumarate [1:1]

A stirred mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran wastreated with 1.8 g (0.01 mole) of 1-benzylpiperazine. After stirring for30 min, approximately 1 g of ice was added and stirring continued for 16hr. The reaction mixture was diluted with 200 ml of water and the oilwhich separated was extracted into methylene chloride (2×50 ml). Thecombined extracts were dried and concentrated in vacuo to yield 4.7 g ofresidue. This residue was dissolved in 10 ml of isopropanol and treatedwith 1.2 g of fumaric acid dissolved in 25 ml of boiling isopropanol.The mixture was concentrated to a pastle-like residue which yielded asolid when triturated with ethyl acetate. Recrystallization from methylethyl ketone yielded 5.2 g (97%) of fine white crystals, m.p. 125°-127°C.

Analysis: Calculated for C₂₂ H₂₄ F₃ N₃ O₂.C₄ H₄ O₄ : C,58.32; H,5.27;N,7.85

Found: C,58.03; H,5.19; H,7.79

EXAMPLE 120 3-[(4-Chlorophenyl)thio]-1-azetidinecarboxamide

A stirred solution of 2.6 g (0.01 mole) of3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 2 ml (0.02 mole) of 57% ammoniumhydroxide. The slightly exothermic reaction mixture was stirred for 3 hras it cooled to ambient temperature then diluted with 200 ml of water.The precipitated product was collected by filtration (2.4 g) andrecrystallized from absolute ethanol to yield 2 g (83.3%) of fine whitecrystals, m.p. 210°-212° C.

Analysis: Calculated for C₁₀ H₁₁ ClN₂ OS: C,49.48; H,4.57; N,11.54

Found: C,49.40; H,4.54; N,11.54

EXAMPLE 121 3-[(4-Chlorophenyl)thio]-N,N-dimethyl-1-azetidinecarboxamide

A solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran wasstirred while cooling in a water bath and treated with 2.5 ml (0.02mole) of 40% dimethylamine in water. After stirring for 3 hr, thereaction mixture was diluted with 200 ml of water and the resultingproduct collected ny filtration (2.6 g). Recrystallization fromacetone/isopropyl ether yielded 2 g (74.1%) of fine white crystals, m.p.96°-97° C.

Analysis: Calculated for C₁₂ H₁₅ ClN₂ OS: C,53.23; H,5.58; N,10.35

Found: C,53.25; H,5.65; N,10.35

EXAMPLE 122 3-[(4-Chlorophenyl)thio]-N-methyl-1-azetidinecarboxamide

A stirred solution of 2.6 g (0.01 mole) of3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was cooled in a water bath and treated with 2 ml (0.02mole) of 40% methylamine in water. After 3 hr, the reaction mixture wasdiluted with 200 ml of water and the precipitated product collected byfiltration (2.6 g). Recrystallization from benzene/methanol yielded 2.4g (93.8%) of fine white crystals, m.p. 161°-162° C.

Analysis: Calculated for C₁₁ H₁₃ ClN₂ OS: C,51.46; H,5.10; N,10.91

Found: C,51.51; H,5.14; N,10.91

EXAMPLE 1233-[(4-Chlorophenyl)thio]-N-(2-propenyl)-1-azetidinecarboxamide

A stirred solution of 2.6 g (0.01 mole) of3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was cooled in a water bath and treated with 2.2 g (0.02mole) of 2-propenylamine. After stirring for 3 hr, the reaction mixturewas diluted with 200 ml of water and the product separated as a yellowoil. The oil slowly solidified to yield a dull orange-red waxy material.After decanting the water and allowing the residue to air dry, theresidue was triturated 5 times with boiling isopropyl ether and thedecanted solutions upon cooling yielded 5 solid fractions, from white topale beige color. The fractions were all consistent with the expectedproduct by mass spectral analysis and TLC showed only a single product.All five fractions were combined to give 1.7 g (60.3%), m.p. 88°-89° C.

Analysis: Calculated for C₁₃ H₁₅ ClN₂ OS: C,55.22; H,5.35; N,9.91

Found: C,55.26; H,5.38; N,9.92

EXAMPLE 1241-[3-[(4-Chlorophenyl)thio]-1-azetidinylcarbonyl]-4-methylpiperazinefumarate [1:1]

A stirred solution of 2.6 g (0.01 mole) of3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 2 g (0.02 mole) of 1-methylpiperazine.After stirring for 16 hr, the reaction mixture was diluted with 200 mlof water and the milky solution was extracted with methylene chloride(2×50 ml). The combined extracts were treated with 1.2 g of fumaric acidin 25 ml of methanol. The resulting precipitate was collected byfiltration (3.1 g) and recrystallized from isopropanol, yielding 2.2 g(49.9%) of fine white crystals, m.p. 173°-174° C.

Analysis: Calculated for C₁₅ H₂₀ ClN₃ OS.C₄ H₄ O₄ : C,51.64; H,5.47;N,9.51

Found C,51.62; H,5.51; N,9.45

EXAMPLE 125 3-[3-(Trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A 16 ml solution containing 5.94 g of phosgene was prepared bydissolving phosgene gas in cold toluene. This solution was stirred with7 g potassium carbonate in an acetone-ice bath for about 10 minutes. Tothis solution in the bath was added dropwise over a 13 minute period at-9° C. to +4° C. a solution of 19.2 g (0.050 mole) of1-(diphenylmethyl)-3-[3-(trifluoromethyl)phenoxy]azetidine in 38.4 ml oftoluene. The cold bath was removed and the temperature of the reactionmixture rose to 18° C. after 1/2 hr. TLC (silica gel eluted withmethylene chloride) of a sample indicated all the1-(diphenylmethyl)-3-[3(trifluoromethyl)phenoxy]azetidine haddisappeared (reacted). After 1 hr, the mixture was filtered to removesolid, leaving a filtrate containing3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride anddiphenylchloromethane. The filtrate was added (over a 7 min period) toabout 30 ml of liquid ammonia at -60°to -30° C. Some white solid formedin the mixture. The ammonia was refluxed under a dry ice-acetonecondenser for 1/2 hr and then allowed to evaporate using nitrogen gas tofacilitate the removal of ammonia. Petroleum ether (60 ml) was added tothe mixture and the resulting white solid was collected by filtrationand rinsed twice with petroleum ether to give 18.1 g of solid. The solidwas stirred in 90 ml of water at room temperature for one hr, filteredoff, rinsed twice with water and dried under vacuum at about 60° C. for2 hr to give 13 g (100%) of title compound.

EXAMPLE 126Octahydro-2-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]pyrrolo[1,2-a]pyrazinefumarate [1:1]

A solution of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was stirred with 1.4 g (0.01 mole) of potassiumcarbonate then treated with the dropwise addition of 1.3 g (0.01 mole)of 1,4-diazabicyclo(4.3.0)nonane. After stirring for 30 minutes,approximately 2 g of ice was added and stirring continued for 64 hr. Thereaction mixture was diluted with 200 ml of water and the oil whichseparated was extracted into methylene chloride (2×50 ml), dried overmagnesium sulfate and concentrated in vacuo to a pale yellow oil (3.9g). This oil was placed in 25 ml of isopropanol and treated with 1.2 gof fumaric acid and heated to give a clear solution. The solvent wasremoved in vacuo and the residue crystallized on standing. The residuewas recrystallized from ethyl acetate with 5% isopropyl ether and frommethyl isobutyl ketone to yield 2.5 g (51.5%) of beige colored crystals,m.p. 102°-110° C.

Analysis: Calculated for C₁₈ H₂₂ F₃ N₃ O₂.C₄ H₄ O₄ : C,54.43; H,5.40;N,8.66

Found C,54.40; H,5.37; N,8.62

EXAMPLE 127 1-[3-(4-Fluorophenoxy)-1-azetidinylcarbonyl]piperazinefumarate [1:1]

A solution of 7.3 g (0.02 mole) of4-[3-(4-fluorophenoxy)-1-azetidinylcarbonyl]-1-(phenylmethyl)piperazinein 150 ml of ethanol was treated with 1 ml of triethylamine and 0.7 g of5% palladium on carbon catalyst and hydrogenated on a Parr apparatus for5 hr at 70° C. After cooling, the catalyst was removed by filtration andthe filtrate concentrated in vacuo to a pale yellow oil (7 g). The oilsolidified and a sample was recrystallized from isopropyl ether, m.p.95°-97° C. A portion of the free base was converted to the fumarate saltand recrystallized from methyl isobutyl ketone yielding 4.7 g of graysolid. A second recrystallization with charcoal treatment fromisopropanol yielded 3.8 g of white crystals, m.p. 161°-162° C.

Analysis: Calculated for C₁₄ H₁₈ FN₃ O₂.C₄ H₄ O₄ : C,54.68; H,5.61;N,10.63

Found C,54.59; H,5.61; N,10.60

EXAMPLE 128Hexahydro-1-methyl-4-[3-[3-(trifluoromethyl)phenoxy]-1-azetidinylcarbonyl]-1H-1,4-diazepinefumarate [1:1]

A stirred mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran wastreated with 1.15 g (0.01 mole) of 1-methylhomopiperazine, and afterstirring for 15 minutes a small piece of ice was added. After stirringfor 15 hr, the reaction mixture was diluted with 200 ml of water and theoil which separated was extracted into methylene chloride (2×50 ml). Thecombined extracts were dried over magnesium sulfate and concentrated invacuo. The residue (3.8 g) was treated with 1.2 g of fumaric acid anddissolved in 20 ml of isopropanol by heating. Upon cooling, theprecipitated solid was collected by filtration to yield 4.1 g (86.6%) ofwhite crystals, m.p. 131°-133° C.

Analysis: Calculated for C₁₇ H₂₂ F₃ N₃ O₂.C₄ H₄ O₄ : C,53.28; H,5.54;N,8.88

Found C,53.18; H,5.56; N,8.83

EXAMPLE 129 CisN,2-Dimethyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 4.02 g (0.01 mole) of crude (73%)2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cisisomer in 20 ml of tetrahydrofuran was treated while stirring with 1.6 g(0.02 mole) of 40% aqueous monomethylamine. After stirring for 6 hr, thereaction mixture was diluted with 100 ml of water and the oil whichseparated was extracted into methylene chloride (2×50 ml). The combinedextracts were dried over magnesium sulfate and concentrated in vacuo(4.2 g). The oil solidified on standing and was recrystallized fromisooctane with a trace of benzene to give 2.6 g (90.3%) of whitecrystalline product, m.p. 89°-91° C.

Analysis: Calculated for C₁₃ H₁₅ F₃ N₂ O₂ : C,54.17; H,5.25; N,9.72

Found: C,54.54; H,5.28; N,9.58

EXAMPLE 130 Cis-2-methyl-N-(2-propenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A stirred mixture of 4.02 g (0.01 mole) of crude (73%)2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cisisomer and 1.4 g (0.01 mole) of potassium carbonate in 20 ml oftetrahydrofuran was treated with 0.57 g (0.01 mole) of 2-propenylamine.After stirring for 15 minutes, a small piece of ice was added andstirring continued for 3 hr. The reaction mixture was diluted with waterand the oil which separated was extracted with methylene chloride (2×50ml). The combined extracts were dried over magnesium sulfate andconcentrated in vacuo (5.2 g). The crude product was chromatographed ona 125 g silica gel column. Elution with chloroform washed impuritiesfrom the column and the product was removed by eluting with an ethylacetate/chloroform gradient (1-20%). The combined product fractions gavea pale yellow oil which solodified on standing and was recrystallizedfrom isopropyl ether/hexane to give an oil which slowly crystallized,yielding 2.1 g (67.8%) of white product, m.p. 74°-77° C.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂ : C,57.32; H,5.45; N,8.91

Found: C,57.30; H,5.40; N,8.91

EXAMPLE 131Cis-2-Methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide

A solution of 4.02 g (0.01 mole) of crude (73%)2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cisisomer in 20 ml of tetrahydrofuran was treated while stirring with 2 ml(0.02 mole) of 57% aqueous ammonium hydroxide. After stirring for 6 hr,the reaction mixture was diluted with 100 ml of water and the oil whichseparated was extracted into methylene chloride (2×50 ml). The combinedextracts were dried over magnesium sulfate and concentrated in vacuo togive 4.2 g. A sample of the oil crystallized at -78° C. and was used toseed the bulk of the material. The resulting solid was recrystallizedfrom benzene/isooctane to yield 2.35 g (87%) of white crystallineproduct, m.p. 107°-108° C.

Analysis: Calculated for C₁₂ H₁₃ F₃ N₂ O₂ : C,52.56; H,4.78; N,10.22

Found: C,52.61; H,4.60; N,10.11

EXAMPLE 132N-Methyl-N-(2-propenyl)-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamidehydrate [1:0.5]

A stirred mixture of 2.8 g (0.01 mole) of3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g(0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran wastreated with 0.72 g (0.01 mole) of N-methylallylamine. After stirringfor 15 minutes, a piece of ice was added and stirring continued for 16hr. The reaction mixture was diluted with water and the oil whichseparated was extracted into methylene chloride (2×50 ml). The combinedextracts were dried over magnesium sulfate and concentrated in vacuo(3.7 g). The crude oil was chromatographed on a 75 g silica gel columnby eluting with chloroform. After the first crude material was washedfrom the column, three product fractions were combined and concentratedin vacuo to yield 3 g (97%) of water-like oil.

Analysis: Calculated for C₁₅ H₁₇ F₃ N₂ O₂.1/2 H₂ O: C,55.73; H,5.62;N,8.66

Found C,55.75; H,5.28; N,8.65

EXAMPLE 133 3-(3-Methoxyphenoxy)-N-methyl-1-azetidinecarboxamide

A solution of 4.8 g (0.02 mole) of3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml oftetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueousmonomethylamine and stirred for 16 hr. The reaction mixture was dilutedwith 200 ml of water and the oil which separated was extracted intomethylene chloride (2×50 ml). The extracts were dried by passing throughWhatman phase separating paper and concentrated in vacuo (3.85 g). Theresidue was purified by chromatography on two 4 mm (silica gel)chromatotron plates by eluting with an ethyl acetate/methylene chloridegradient to give 0.98 g (21%) of tan solid. Recrystallization frombenzene with a trace of ligroin yielded 600 mg of tan crystallinepowder, m.p. 109°-111° C.

Analysis: Calculated for C₁₂ H₁₆ N₂ O₃ : C,61.00; H,6.83; N,11.86

Found: C,61.85; H,6.87; N,11.46

EXAMPLE 1344-[3-(4-Fluorophenoxy)-1-azetidinylcarbonyl]-1-piperazinecarboxylic acidethyl ester

A stirred mixture of 2.8 g (0.01 mole) of1-[3-(4-fluorophenoxy)-1-azetidinylcarbonyl]piperazine and 1.4 g (0.01mole) of potassium carbonate in 20 ml of tetrahydrofuran was treatedwith 1.1 g (0.01 mole) of ethyl chloroformate. After stirring for 15minutes, a small piece of ice was added and stirring continued for 72hr. The reaction mixture was diluted with water and the oil whichseparated solidified on standing. The solid residue was purified bycolumn chromatography (silica gel; washed with chloroform and elutedwith ethyl acetate) to give the product 2.5 g (71%) which wasrecrystallized from benzene/ligroin to yield 2.35 g (66.7%) of whitecrystalline product, m.p. 89°-90° C.

Analysis: Calculated for C₁₇ H₂₂ FN₃ O₄ : C,58.11; H,6.31; N,11.96

Found: C,58.29; H,6.49; N,11.87

                                      TABLE 1                                     __________________________________________________________________________     ##STR21##                                                                    Ex. No.                                                                            Ar           B R.sup.3                                                                            Z NR.sup.1 R.sup.2   Salt    Geometric               __________________________________________________________________________                                                          Isomer                   1   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    S NHCH.sub.3         --      --                       2   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    S NH[2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3]                                                          --      --                       3   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2C.sub.6 H.sub.5 ]                                                                     --      --                       4   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    S NH[2,6-(Cl).sub.2 C.sub.6 H.sub.3]                                                               --      --                       5   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    S NH[(CH.sub.2).sub.3N(C.sub.2 H.sub.5).sub.2                                                      oxalate [1:1]                                                                         --                       6   3-CF.sub.3C.sub. 6 H.sub.4                                                                 O H    S NH[(CH.sub.2).sub.3N(CH.sub.3).sub.2 ]                                                           --      --                       7   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2CHCH.sub.2 ]                                                                          --      --                       8   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O cyclopropylamino   --      --                       9   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[(CH.sub.2).sub.3N(C.sub.2 H.sub.5).sub.2                                                      oxalate [1:1.5]                 10   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2CHCH.sub.2 ]                                                                          --      --                      11   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O (cyclopropylmethyl)amino                                                                         --      --                      12   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O N(C.sub.2 H.sub.5).sub.2                                                                         --      --                      13   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O N(CH.sub.3).sub.2  --      --                      14   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.2CCH)    --      --                      15   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O cyclohexylamino    --      --                      16   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O cyclopropylamino   --      --                      17   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O (cyclopropylmethyl)amino                                                                         --      --                      18   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    S NH[(CH.sub.2).sub.3N(C.sub.2 H.sub.5).sub.2                                                      --      --                      19   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[(CH.sub.2).sub.3N(C.sub.2 H.sub.5).sub.2                                                      oxalate [1:2]                                                                         --                      20   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.2CCH)    --      --                      21   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2C(CH.sub.3)(CH.sub.2)]                                                                --      --                      22   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2C(CH.sub.3)(CH.sub.2)]                                                                --      --                      23   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2CHC(CH.sub.3).sub.2 ]                                                                 --      --                      24   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2CHC(CH.sub.3).sub.2 ]                                                                 --      --                      25   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.2CHCHCH.sub.3)                                                                         --      E                       26   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.2CHCHCH.sub.3)                                                                         --      E                       27   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(C.sub.6 H.sub.5)                                                                              --      --                      28   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(C.sub.6 H.sub.5)                                                                              --      --                      29   3-CF.sub.3C.sub.6 H.sub.4                                                                  O CH.sub.3                                                                           O NH(CH.sub.3)       --      Trans                   30   3-CF.sub.3C.sub.6 H.sub.4                                                                  O CH.sub.3                                                                           O NH.sub.2           --      Trans                   31   3-CF.sub.3C.sub.6 H.sub.4                                                                  O CH.sub.3                                                                           O NH(CH.sub.2CHCH.sub.2)                                                                           --      Trans                   32   3-ClC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.3)       --      --                      33   3-ClC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      34   pyridin-2-yl O H    O NH(CH.sub.3)       --      --                      35   pyridin-2-yl O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      36   pyridin-2-yl O H    O NH.sub.2                                           37   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-(1-propyl)-1-piperazinyl                                                                       fumarate [1:1]                                                                        --                      38   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 1H-imidazole       --      --                      39   C.sub.6 H.sub.5                                                                            O H    O NH(CH.sub.3)       --      --                      40   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.3)       --      --                      41   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.3)       --      --                      42   2-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.3)       --      --                      43   2-[C(O)NH.sub.2 ]C.sub.6 H.sub.4                                                           O H    O NH(CH.sub.3)       --      --                      44   3-[C(O)NH.sub.2 ]C.sub.6 H.sub.4                                                           O H    O NH(CH.sub.3)       --      --                      45   4-[C(O)NH.sub.2 ]C.sub.6 H.sub.4                                                           O H    O NH(CH.sub.3)       --      --                      46   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH.sub.2           --      --                      47   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(C.sub.2 H.sub.5)                                                                              --      --                      48   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH(CH.sub.3).sub.2 ]                                                                          --      --                      49   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[(CH.sub.2).sub.2CH.sub.3 ]                                                                    --      --                      50   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[(CH.sub.2).sub.3CH.sub.3 ]                                                                    --      --                      51   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(C.sub.2 H.sub.5)                                                                              --      --                      52   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[(CH.sub.2).sub.3CH.sub.3 ]                                                                    --      --                      53   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[(CH.sub.2).sub.2CH.sub.3 ]                                                                    --      --                      54   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH.sub.2           --      --                      55   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH(CH.sub.3).sub.2 ]                                                                          --      --                      56   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[C(CH.sub.3).sub.3 ]                                                                           --      --                      57   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2CH(CH.sub.3).sub.2 ]                                                                  --      --                      58   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[C(CH.sub.3).sub.3 ]                                                                           --      --                      59   4-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH[CH.sub.2CH(CH.sub.3).sub.2 ]                                                                  --      --                      60   3-ClC.sub.6 H.sub.4                                                                        O H    O NH.sub.2           --      --                      61   3-FC.sub.6 H.sub.4                                                                         O H    O NH(CH.sub.3)       --      --                      62   3-FC.sub.6 H.sub.4                                                                         O H    O NH(CH.sub.3)       --      --                      63   3-FC.sub.6 H.sub.4                                                                         O H    O NH.sub.2           --      --                      64   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 1-homopiperidinyl  --      --                      65   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 1-piperidinyl      --      --                      66   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 1-azetidine        --      --                      67   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 1-pyrrolidine      --      --                      68   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O N(CH.sub.3)(CH.sub.2CHCH)                                                                        --      --                      69   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-methyl-1-piperazinyl                                                                           oxalate [1:1.5]                                                                       --                      70   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-methyl-1-piperazinyl                                                                           fumarate [1:1]                                                                        --                      71   3-CF.sub. 3C.sub.6 H.sub.4                                                                 O H    O NH(4-CH.sub.3C.sub.6 H.sub.4)                                                                    --      --                      72   3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(4-ClC.sub.6 H.sub.4)                                                                          --      --                      73   4-FC.sub.6 H.sub.4                                                                         O H    O NH(CH.sub.3)       --      --                      74   4-FC.sub.6 H.sub.4                                                                         O H    O NH.sub.2           --      --                      75   4-FC.sub.6 H.sub.4                                                                         O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      76   4-FC.sub.6 H.sub.4                                                                         O H    O NH(CH.sub.2CCH)    --      --                      77   3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O NH(CH.sub.3)       --      --                      78   3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      79   3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O NH(CH.sub.2CCH)    --      --                      80   4-ClC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.2CCH)    --      --                      81   3-BrC.sub.6 H.sub.4                                                                        O H    O NH.sub.2           --      --                      82   3-BrC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.3)       --      --                      83   3-BrC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      84   3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O NH.sub.2           --      --                      85   4-ClC.sub.6 H.sub.4                                                                        O H    O NH.sub.2           --      --                      86   4-ClC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.3)       --      --                      87   4-ClC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      88   3-BrC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.2CCH)    --      --                      89   4-BrC.sub.6 H.sub. 4                                                                       O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      90   4-BrC.sub.6 H.sub.4                                                                        O H    O NH.sub.2           --      --                      91   4-BrC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.3)       --      --                      92   4-BrC.sub.6 H.sub.4                                                                        O H    O NH(CH.sub.2CCH)    --      --                      93   3-CH.sub.3C.sub.6 H.sub.4                                                                  O H    O NH.sub.2           --      --                      94   3-CH.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      95   3-CH.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.2CCH)    --      --                      96   3-(OCH.sub.3)C.sub.6 H.sub.4                                                               O H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      97   3-(OCH.sub.3)C.sub.6 H.sub.4                                                               O H    O NH(CH.sub.2C CH)   --      --                      98   3-CH.sub.3C.sub.6 H.sub.4                                                                  O H    O NH(CH.sub.3)       --      --                      99   C.sub.6 H.sub.5                                                                            O H    O NH.sub.2           --      --                      100  4-BrC.sub.6 H.sub.4                                                                        O H    O 4-phenyl-1-piperazinyl                                                                           --      --                      101  4-BrC.sub.6 H.sub.4                                                                        O H    O 4-(phenylmethyl)-1-piperazinyl                                                                   --      --                      102  4-BrC.sub.6 H.sub.4                                                                        O H    O 4-methyl-1-piperazinyl                                                                           fumarate [1:1]                                                                        --                      103  3-BrC.sub.6 H.sub.4                                                                        O H    O 4-methyl-1-piperazinyl                                                                           fumarate [1:1]                                                                        --                      104  4-FC.sub.6 H.sub.4                                                                         O H    O 4-methyl-1-piperazinyl                                                                           fumarate [1:1]                                                                        --                      105  4-FC.sub.6 H.sub.4                                                                         O H    O 4-phenyl-1-piperazinyl                                                                           --      --                      106  4-FC.sub.6 H.sub.4                                                                         O H    O 4-(phenylmethyl)-1-piperazinyl                                                                   --      --                      107  4-FC.sub.6 H.sub.4                                                                         O H    O 4-(phenylmethyl)-1-piperazinyl                                                                   fumarate [1:1]                                                                        --                      108  3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O 4-methyl-1-piperazinyl                                                                           fumarate [1:1]                                                                        --                      109  3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O 4-(phenylmethyl)-1-piperazinyl                                                                   fumarate [1:1]                                                                        --                      110  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-phenyl-1-piperazinyl                                                                           --      --                      111  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-(2-pyridinyl)-1-piperazinyl                                                                    --      --                      112  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-phenyl-1-piperidinyl                                                                           --      --                      113  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 1,2,3,6-tetrahydro-4-phenyl-1-pyridinyl                                                          --      --                      114  3,4-(Cl).sub.2C.sub.6 H.sub.3                                                              O H    O 4-(2-pyridinyl)-1-piperazinyl                                                                    --      --                      115  3-BrC.sub.6 H.sub.4                                                                        O H    O 4-(phenylmethyl)-1-piperazinyl                                                                   fumarate [1:1]                                                                        --                      116  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-(4-ClC.sub.6 H.sub.4)-4-(OH)-1-piperidinyl                                                     --      --                      117a 3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-[2-(OCH.sub.3)C.sub.6 H.sub.4]-1-piperazinyl                                                   fumarate                        117b 3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-[3-(CF.sub.3)C.sub.6 H.sub.4]-1-piperazinyl                                                    fumarate                                                                              --                      117c 3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 2,6-(CH.sub.3).sub.2 -4-morpholinyl                                                              --      --                      117d 3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 3,5-(CH.sub.3).sub.2 -4-morpholinyl                                                              --      --                      117e 3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-morpholinyl      --      --                      118  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-(2-pyrimidine)-1-piperazinyl                                                                   --      --                      119  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-(phenylmethyl)-1-piperazinyl                                                                   fumarate [1:1]                                                                        --                      120  4-ClC.sub.6 H.sub.4                                                                        S H    O NH.sub.2           --      --                      121  4-ClC.sub.6 H.sub.4                                                                        S H    O N(CH.sub.3).sub.2  --      --                      122  4-ClC.sub.6 H.sub.4                                                                        S H    O NH(CH.sub.3)       --      --                      123  4-ClC.sub.6 H.sub.4                                                                        S H    O NH(CH.sub.2CHCH.sub.2)                                                                           --      --                      124  4-ClC.sub.6 H.sub.4                                                                        S H    O 4-methyl-1-piperazinyl                                                                           fumarate [1:1]                                                                        --                      125  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O NH.sub.2           --      --                      126  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O                                                                                ##STR22##         fumarate [1:1]                                                                        --                      127  4-FC.sub.6 H.sub.4                                                                         O H    O 1-piperazinyl      fumarate [1:1]                                                                        --                      128  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O 4-methyl-1-homopiperazinyl                                                                       fumarate [1:1]                                                                        --                      129  3-CF.sub.3C.sub.6 H.sub.4                                                                  O CH.sub.3                                                                           O NH(CH.sub.3)       --      cis                     130  3-CF.sub.3C.sub.6 H.sub.4                                                                  O CH.sub.3                                                                           O NH(CH.sub.2CHCH.sub.2)                                                                           --      cis                     131  3-CF.sub.3C.sub.6 H.sub.4                                                                  O CH.sub.3                                                                           O NH.sub.2           --      cis                     132  3-CF.sub.3C.sub.6 H.sub.4                                                                  O H    O N(CH.sub.3)(CH.sub.2CHCH.sub.2)                                                                  hydrate [1:0.5]                                                                       --                      133  3-(OCH.sub.3)C.sub.6 H.sub.4                                                               O H    O NH(CH.sub.3)       --      --                      134  4-F C.sub.6 H.sub.4                                                                        O H    O 4-(C(O)OC.sub.2 H.sub.5)-1-piperazinyl                                                           --      --                      __________________________________________________________________________

Pharmacological Test Procedures Muscle Relaxant Test

The test procedure relied on to indicate positive muscle relaxantactivity is the morphine-Induced Straub Tail in Mice Test described byG. D. Novak in DRUG DEVELOPMENT RESEARCH (1982) 2: 383-386, except 8animals per group were used per test rather than 10. The test issummarized as follows: The test drug, reference drug, and controlarticles to be administered are prepared in saline, 0.5% aqueousmethylcellulose suspension or other, depending on solubility, in suchconcentration that the volume administered is 10 ml/kg. The initialscreening dose of the test drug is usually 100 mg/kg. Groups of 8 miceare given an IP dose of a compound or vehicle prepared as describedabove. After 15 min, mice are administered morphine sulfate, 60 mg/kg,subcutaneously. Fifteen minutes after administration of morphine (i.e.,30 min after test compound administration), mice were scored forpresence of Straub Tail defined as an elevation of the tail at least 90degrees from the horizontal. An ED₅₀ value may be determined from atleast three logarithmically spaced doses by the method of Litchfield andWilcoxon (1949), J. PHARMACOL. EXP. THER. 96: 99-113. Compared to areference compound, methocarbamol, which exhibited an ED₅₀ of 75-110 inthe above Straub Tail Test, the more active compounds of Formula I were5-10 times more active.

Antianxiety Test

The test screening procedure relied on to indicate positive antianxietyresponse is a modification of the Vogel Conflict Test which is based onshock-suppressed drinking behavior in rats outlined by J. R. Vogel, etal in PSYCHOPHARMACOLOGY 21: 1-7 (1971). The procedure used is asfollows: The test reference and control articles to be administeredintraperitoneally in physiological saline, 0.5% aqueous methylcelluloseor other depending on a solubility in such concentration that the volumeadministered is 5 ml/kg. The initial screening dose of the test articleis usually 100.0 mg/kg initially, and the reference drug (diazepam) is 5mg/kg.

Prior to dosing, rats are housed 2 per cage and deprived of water for 48hr and thereafter randomized into treatment groups of five. Feed isavailable ad libitum. Thirty minutes after dosing, each rat is placedindividually in a plexiglass cage measuring 18 cm in width, 13 cm inheight and 29.5 cm in length and equipped with a stainless steel gridfloor. The cage is covered with a plastic lid containing holes tofacilitate introduction of a water bottle (30 ml plastic centrifugetube) with a rubber stopper and metal drinking tube. A Drinkometercircuit (Omniteck Electronics, Inc., 3000 Cortona Road, Columbus, Ohio43204, is connected between the drinking tube and the grid floor of theapparatus so that the rat completes the circuit whenever it licks thetube. The procedure is to allow the rat to find the drinking tube andcomplete 20 licks (as displayed on the Drinkometer digital readout)prior to the start of the experimental session. Rats not reaching thiscriterion are discarded. A three minute experimental session isinitiated by a 0.25 mA shock at the 20th lick. Rats that continuedrinking will experience a shock at each successive 20th lick. The totalnumber of shocks during the experimental session are recorded asfollows: ##EQU1## Statistical analysis is performed by the Dunn'sMultiple Comparison Test described by O. J. Dunn (1964) TECHNOMETRICS6(3):241-52. The mean number of shocks experienced by the control groupis compared with those of each drug-treated group. Significance isconsidered at P<0.1. The higher the total shocks compared to control,the more active is the compound. Active compounds may then be similarlytested at reduced dosages. Illustratively, one preferred compound, thecompound of Example 16, namely,N-cyclopropyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide wasactive at as low a dosage as 10 mg per kg, where total number of shockstaken as calculated above over control was 14/4.6 (P=0.03) compared toabout 12-15/4 for diazepam.

Pharmaceutical Compositions

The methods of treating anxiety, muscle tension, and spasticity inmammals is best carried out by administering as active ingredients in apharmaceutical composition at least one of the compounds of Formula I inassociation with a pharmaceutical carrier or excipient. The compoundsare thus presented in a therapeutic composition suitable for oral,rectal, parenteral, subcutaneous, intramuscular, intraperitoneal, orintravenous administration. Thus, for example, the composition for oraladministration can take the form of elixirs, capsules, tablets, orcoated tablets containing carriers conveniently used in thepharmaceutical art. Suitable tableting excipients include lactose,potato, and maize starches, talc, gelatin, stearic and silicic acids,magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration, the carrier can be comprised of a sterileparenterally acceptable liquid; e.g., water or arachis oil contained inampoules.

In compositions for rectal administration, the carrier can be comprisedof a suppository base, e.g., cocoa butter or glyceride.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of preferred dosage forms according to the invention. It isonly necessary that the active ingredient constitute an effectiveamount; i.e., such that a suitable effective dosage will be consistentwith the dosage form employed. The exact individual dosages as well asdaily dosages will, of course, be determined according to standardmedical principles under the direction of a physician or veterinarian.

Testing suggests that compounds of Formula I will be effective in manfor muscle relaxant effects at about 4-40 mg/kg body weight per day.Illustratively, one compound, namely,N-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidine carboxamide (Example41), was found to be about 5 times as potent as Methocarbamol as amuscle relaxant.

The suggested regimen, for example, for the compound of Example 41 as amuscle relaxant appears to be about 10 mg/kg/day or for a 75 kgindividual about a unit dosage of 250 mg, t.i.d.

Effective daily dosages of compounds of Formula I as antianxiety agentsare projected to be about 1-10 mg/kg/day body weight based on animaldata.

What is claimed is:
 1. A 3-aryloxyazetidinecarboxamide compound selectedfrom the group having the formula: ##STR23## wherein: Ar is phenyl orphenyl substituted by chloro, bromo, iodo, fluoro, loweralkyl,loweralkoxy, nitro, aminocarbonyl or trifluoromethyl;R³ is H orloweralkyl; R¹ is C₃ -C₉ cycloalkyl, allyl, 2-methyl-2-propenyl,propargyl, phenyl or phenyl substituted by halogen, loweralkyl,loweralkoxy, nitro, cyano, or trifluoromethyl; and R² is H.
 2. Acompound according to claim 1 wherein R³ is methyl.
 3. A compoundaccording to claim 1 wherein R¹ is selected from the group consisting ofallyl, 2-methylallyl, propargyl and C₃ -C₉ cycloalkyl.
 4. A compoundaccording to claim 1 which isN-cyclopropyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide. 5.A compound according to claim 1 which isN-(2-propenyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide. 6.A compound according to claim 1 which isN-cyclopropyl-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide. 7.A compound according to claim 1 which isN-(2-propynyl)-3-[4-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide. 8.A compound according to claim 1 which is3-(3-chlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide.
 9. A compoundaccording to claim 1 which is3-(4-fluorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide.
 10. Acompound according to claim 1 which is3-(4-chlorophenoxy)-N-(2-propenyl)-1-azetidinecarboxamide.